Aspartyl protease inhibitors

ABSTRACT

Disclosed are compounds of the formula I 
                         
or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein j, k, U, W, R, R 1 , R 2 , R 3 , R 4 , R 6 , R 7  and R 7a  are as described above in the specification.
 
     Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases. Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic m 1  agonist or m 2  antagonist.

RELATED APPLICATIONS

This application claims priority to provisional application U.S. Ser.No. 60/690,537, filed on Jun. 14, 2005, herein incorporated byreference.

FIELD OF THE INVENTION

This invention relates to aspartyl protease inhibitors, pharmaceuticalcompositions comprising said compounds, their use in the treatment ofcardiovascular diseases, cognitive and neurodegenerative diseases, andtheir use as inhibitors of the Human Immunodeficiency Virus,plasmepsins, cathepsin D and protozoal enzymes.

BACKGROUND

There are a number of aspartic proteases known to date, including pepsinA and C, renin, BACE, BACE 2, Napsin A, and cathepsin D, which have beenimplicated in pathological conditions. The role of renin-angiotensinsystem (RAS) in regulation of blood pressure and fluid electrolyte hasbeen well established (Oparil, S, et al. N Engl J Med 1974;291:381-401/446-57). The octapeptide Angiotensin-II, a potentvasoconstrictor and stimulator for release of adrenal aldosterone, wasprocessed from the precursor decapeptide Angiotensin-I, which in turn isprocessed from angiotensinogen by the renin enzyme. Angiotensin-II isalso found to play roles in vascular smooth muscle cell growth,inflammation, reactive oxygen species generation and thrombosis andinfluence atherogenesis and vascular damage. Clinically, the benefit ofinterruption of the generation of angiotensin-II through antagonism ofconversion of angiotensin-I has been well known and there are a numberof ACE inhibitor drugs on the market. The blockade of the earlierconversion of angiotensinogen to angiotensin-I, i.e. the inhibition ofrenin enzyme, is expected to have similar but not identical effects.Since renin is an aspartyl protease whose only natural substrate isangiotensinogen, it is believed that there would be less frequentadverse effect for controlling high blood pressure and related symptomsregulated by angiotensin-II through its inhibition.

Another protease, Cathepsin-D, is involved in lysosomal biogenesis andprotein targeting, and may also be involved in antigen processing andpresentation of peptide fragments. It has been linked to numerousdiseases including, Alzheimer's, Disease, connective tissue disease,muscular dystrophy and breast cancer.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease thatis ultimately fatal. Disease progression is associated with gradual lossof cognitive function related to memory, reasoning, orientation andjudgment. Behavioral changes including confusion, depression andaggression also manifest as the disease progresses. The cognitive andbehavioral dysfunction is believed to result from altered neuronalfunction and neuronal loss in the hippocampus and cerebral cortex. Thecurrently available AD treatments are palliative, and while theyameliorate the cognitive and behavioral disorders, they do not preventdisease progression. Therefore there is an unmet medical need for ADtreatments that halt disease progression.

Pathological hallmarks of AD are the deposition of extracellularβ-amyloid (Aβ) plaques and intracellular neurofibrillary tanglescomprised of abnormally phosphorylated protein tau. Individuals with ADexhibit characteristic Aβ deposits, in brain regions known to beimportant for memory and cognition. It is believed that Aβ is thefundamental causative agent of neuronal cell loss and dysfunction whichis associated with cognitive and behavioral decline. Amyloid plaquesconsist predominantly of Aβ peptides comprised of 40-42 amino acidresidues, which are derived from processing of amyloid precursor protein(APP). APP is processed by multiple distinct protease activities. Aβpeptides result from the cleavage of APP by β-secretase at the positioncorresponding to the N-terminus of Aβ, and at the C-terminus byγ-secretase activity. APP is also cleaved by α-secretase activityresulting in the secreted, non-amyloidogenic fragment known as solubleAPP.

An aspartyl protease known as BACE-1 has been identified as theβ-secretase activity responsible for cleavage of APP at the positioncorresponding to the N-terminus of Aβ peptides.

Accumulated biochemical and genetic evidence supports a central role ofAβ in the etiology of AD. For example, Aβ has been shown to be toxic toneuronal cells in vitro and when injected into rodent brains.Furthermore inherited forms of early-onset AD are known in whichwell-defined mutations of APP or the presenilins are present. Thesemutations enhance the production of Aβ and are considered causative ofAD.

Since Aβ peptides are formed as a result of β-secretase activity,inhibition of BACE-1 should inhibit formation of Aβ peptides. Thusinhibition of BACE-1 is a therapeutic approach to the treatment of ADand other cognitive and neurodegenerative diseases caused by Aβ plaquedeposition.

Human immunodeficiency virus (HIV), is the causative agent of acquiredimmune deficiency syndrome (AIDS). It has been clinically demonstratedthat compounds such as indinavir, ritonavir and saquinavir which areinhibitors of the HIV aspartyl protease result in lowering of viralload. As such, the compounds described herein would be expected to beuseful for the treatment of AIDS. Traditionally, a major target forresearchers has been HIV-1 protease, an aspartyl protease related torenin.

In addition, Human T-cell leukemia virus type I (HTLV-I) is a humanretrovirus that has been clinically associated with adult T-cellleukemia and other chronic diseases. Like other retroviruses, HTLV-Irequires an aspartyl protease to process viral precursor proteins, whichproduce mature virions. This makes the protease an attractive target forinhibitor design. (Moore, et al. Purification of HTLV-I Protease andSynthesis of Inhibitors for the treatment of HTLV-I Infection 55^(th)Southeast Regional Meeting of the American Chemical Society, Atlanta,Ga., US Nov. 16-19, 2003 (2003), 1073. CODEN; 69EUCH Conference, AN2004:137641 CAPLUS).

Plasmepsins are essential aspartyl protease enzymes of the malarialparasite. Compounds for the inhibition of aspartyl proteasesplasmepsins, particularly I, II, IV and HAP, are in development for thetreatment of malaria. (Freire, et al. WO 2002074719. Na Byoung-Kuk, etal., Aspartic proteases of Plasmodium vivax are highly conserved in wildisolates, Korean Journal of Parasitology (2004 June), 42(2) 61-6.Journal code: 9435800) Furthermore, compounds used to target aspartylproteases plasmepsins (e.g. I, II, IV and HAP), have been used to killmalarial parasites, thus treating patients thus afflicted.

Compounds that act as aspartyl protease inhibitors are described, forexample in application U.S. Ser. No. 11/010,772, filed on Dec. 13, 2004,herein incorporated by reference.

WO/9304047, herein incorporated by reference, describes compounds havinga quinazolin-2-(thi)one nucleus. The document alleges that the compoundsdescribed therein are inhibitors of HIV reverse transcriptase.

US Publication No. US 2005/0282826 A1, herein incorporated by reference,describes diphenylimidazopyrimidine or -imidazole amines, which are saidto be useful for the therapeutic treatment, prevention or ameliorationof a disease or disorder characterized by elevated β-amyloid deposits orβ-amyloid levels in a patient. Disease states mentioned in thepublication include Alzheimer's disease, mild cognative impairment,Down's syndrome, hereditary cerebral hemorrhage with amyloidosis of theDutch type, cerebral amyloid angiopathy and degenerative dementia.

US Publication No. US 2005/0282825 A1, herein incorporated by reference,describes amino-5,5-diphenylimidazolones, which are said to be usefulfor the therapeutic treatment, prevention or amelioration of a diseaseor disorder characterized by elevated β-amyloid deposits or β-amyloidlevels in a patient. Disease states mentioned in the publication includeAlzheimer's disease, mild cognative impairment, Down's syndrome,hereditary cerebral hemorrhage with amyloidosis of the Dutch type,cerebral amyloid angiopathy and degenerative dementia.

Other publications that disclosed compounds that are useful for treatingAlzheimer's disease include WO 2006/044492, which disclosesspiropiperidine compounds that are said to be inhibitors of β-secretase,and WO 2006/041404, which discloses substituted amino compounds that aresaid to be useful for the treatment or prophylaxix of Aβ relatedpathologies. Both these publications are incorporated by reference.

SUMMARY OF THE INVENTION

The present invention relates to compounds having the structural formulaI

or a stereoisomer, tautomer, or pharmaceutically acceptable salt orsolvate thereof, wherein

j is 0 or 1;

k is 0 or 1, provided that when k is 1, U cannot be —N—;

W is a bond, —C(═S)—, —S(O)—, —S(O)₂—, —C(═O)—, —O—, —C(R⁶)(R⁷)—,—N(R⁵)—, —C(R⁶)(R⁷)C(═O)—, or —C(═N(R⁵))—;

U is —N— or —C(R⁶)—;

R is 1 to 5 R²¹ groups;

R¹, R² and R⁵ are independently selected from the group consisting of H,alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —OR¹⁵, —CN, —C(═NR¹¹)R⁸, —C(O)R⁸,—C(O)OR⁹, —S(O)R¹⁰, —S(O)₂R¹⁰, —C(O)N(R¹¹)(R¹²), —S(O)N(R¹¹)(R¹²),—S(O)₂N(R¹¹)(R¹²), —NO₂, —N═C(R⁸)₂ and —N(R¹¹)(R¹²), provided that R¹and R⁵ are not both selected from —NO₂, —N═C(R⁸)₂ and —N(R¹¹)(R¹²);

R³, R⁶ and R⁷ are independently selected from the group consisting of H,alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CH₂—O—Si(R⁹)(R¹⁰)(R¹⁹), —SH, —CN,—OR⁹, —C(O)R⁸, —C(O)OR⁹, —C(O)N(R¹¹)(R¹²), —SR¹⁹, —S(O)N(R¹¹)(R¹²),—S(O)₂N(R¹¹)(R¹²), —N(R¹¹)(R¹²), —N(R¹¹)C(O)R⁸, —N(R¹¹)S(O)R¹⁰,—N(R¹¹)S(O)₂R¹⁰, —N(R¹¹)C(O)N(R¹²)(R¹³), —N(R¹¹)C(O)OR⁹ and —C(═NOH)R⁸;

R⁴ and R^(7a) are independently selected from the group consisting of abond, alkylene, arylalkylene, heteroarylalkylene, cycloalkylalkylene,heterocycloalkylalkylene, arylcycloalkylalkylene,heteroarylcycloalkylalkylene, arylheterocycloalkylalkylene,heteroarylheterocycloalkylalkylene, cycloalkylene, arylcycloalkylene,heteroarylcycloalkylene, heterocycloalkylene, arylheterocycloalkylene,heteroarylheterocycloalkylene, alkenylene, arylalkenylene,cycloalkenylene, arylcycloalkenylene, heteroarylcycloalkenylene,heterocycloalkenylene, arylheterocycloalkenylene,heteroarylheterocycloalkenylene, alkynylene, arylalkynylene, arylene,cycloalkylarylene, heterocycloalkylarylene, cycloalkyenylarylene,cycloalkenylarylene, heterocycloalkenylarylene, heteroarylene,cycloalkylheteroarylene, heterocycloalkylheteroarylene,cycloalkenylheteroarylene and heterocycloalkenylheteroarylene, with theproviso that both R⁴ and R^(7a) are not both a bond;

R⁴ and R^(7a) together can be a C₁ to C₈ carbon chain, wherein,optionally, one, two or three ring carbons can be replaced by —O—,—C(O)—, —C(S)—, —S—, —S(O)—, —S(O)₂— or —N(R⁵)—, and R⁴ and R^(7a)together with the carbon atoms to which they are attached, form a 3 to 8membered ring, optionally substituted by R, with the following provisos:

that when at least one of the carbons is replaced by —O—, —C(O)—,—C(S)—, —S—, —S(O)—, —S(O)₂— or —N(R⁵)—, then the number of carbons inthe R⁴ and R^(7a) portion of the chain that bonds with U is b, wherein bis 0 to 5, and the number of carbons that are in the R⁴ and R^(7a)portion of the chain that bonds with the carbon of —C(R³)— is c, whereinc is 0 to 5;

that when j is 0 or 1, at least one of the ring carbons must be replacedby —O—, —C(O)—, —C(S)—, —S—, —S(O)—, —S(O)₂— or —N(R⁵)—;

that when j is 0 or 1 and only one ring carbon is replaced with —O—,—C(O)—, —C(S)—, —S—, —S(O)—, —S(O)₂— or —N(R⁵)—, R⁴ and R^(7a) cannotform a cycloalkylether;

R⁸ is independently selected from the group consisting of H, alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —OR¹⁵, —N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶,—N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) and —N(R¹⁵)C(O)OR¹⁶;

R⁹ is independently selected from the group consisting of H, alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl, andheterocycloalkenylheteroaryl;

R¹⁰ is independently selected from the group consisting of H, alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl and —N(R¹⁵)(R¹⁶);

R¹¹, R¹² and R¹³ are independently selected from the group consisting ofH, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —C(O)R⁸, —C(O)OR⁹, —S(O)R¹⁰, —S(O)₂R¹⁰,—C(O)N(R¹⁵)(R¹⁶), —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶) and —CN;

R¹⁵, R¹⁶ and R¹⁷ are independently selected from the group consisting ofH, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, R¹⁸-alkyl, R¹⁸-arylalkyl,R¹⁸-heteroarylalkyl, R¹⁸-cyloalkylalkyl, R¹⁸-heterocycloalkylalkyl,R¹⁸-arylcycloalkylalkyl, R¹⁸-heteroarylcycloalkylalkyl,R¹⁸-arylheterocycloalkylalkyl, R¹⁸-heteroarylheterocycloalkylalkyl,R¹⁸-cycloalkyl, R¹⁸-arylcycloalkyl, R¹⁸-heteroarylcycloalkyl,R¹⁸-heterocycloalkyl, R¹⁸-arylheterocycloalkyl,R¹⁸-heteroarylheterocycloalkyl, R¹⁸-alkenyl, R¹⁸-arylalkenyl,R¹⁸-cycloalkenyl, R¹⁸-arylcycloalkenyl, R¹⁸-heteroarylcycloalkenyl,R¹⁸-heterocycloalkenyl, R¹⁸-arylheterocycloalkenyl,R¹⁸-heteroarylheterocycloalkenyl, R¹⁸-alkynyl, R¹⁸-arylalkynyl,R¹⁸-aryl, R¹⁸-cycloalkylaryl, R¹⁸-heterocycloalkylaryl,R¹⁸-cycloalkenylaryl, R¹⁸-heterocycloalkenylaryl, R¹⁸-heteroaryl,R¹⁸-cycloalkylheteroaryl, R¹⁸-heterocycloalkylheteroaryl,R¹⁸-cycloalkenylheteroaryl, and R¹⁸-heterocycloalkenylheteroaryl; or

-   -   R¹⁵, R¹⁶ and R¹⁷ are

wherein R²³ numbers 0 to 5 substituents, m is 0 to 6 and n is 0 to 5;

R¹⁸ is 1-5 substituents independently selected from the group consistingof alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —NO₂, halo, HO-alkoxyalkyl, —CF₃, —CN,alkyl-CN, —C(O)R¹⁹, —C(O)OH, —C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂,—C(O)NH₂—C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl),—SR¹⁹, —S(O)₂R²⁰, —S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl),—S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocycloalkyl),—S(O)₂N(alkyl)₂, —S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰,—O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂,—NHR²⁰, —N(alkyl)₂, —N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl),—NHC(O)R²⁰, —NHC(O)NH₂, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl),—N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰,—NHS(O)₂NH(alkyl), —NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

or two R¹⁸ moieties on adjacent carbons can be linked together to form

R¹⁹ is alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl orheterocycloalkenylheteroaryl;

R²⁰ is halo substituted aryl, alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl, cycloalkenylheteroarylor heterocycloalkenylheteroaryl,

and wherein each of the alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, in R, R¹, R², R³,R⁴, R⁵, R⁶, R⁷; R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³

are independently unsubstituted or substituted by 1 to 5 R²¹ groupsindependently selected from the group consisting of alkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CN, —C(═NR¹¹)R¹⁵, —OR¹⁵, —C(O)R¹⁵,—C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),-alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶,—S(O)R¹⁵, —N₃, —NO₂ and —S(O)₂R¹⁵;

and wherein each of the alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl, cycloalkenylheteroaryland heterocycloalkenylheteroaryl groups in R²¹ are independentlyunsubstituted or substituted by 1 to 5 R²² groups independently selectedfrom the group consisting of alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, halo, —CF₃, —CN,—C(═NR¹¹)R¹⁵, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, -alkyl-C(O)OR¹⁵,—C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶) —S(O)₂N(R¹⁵)(R¹⁶),—C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶),—N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶,—CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷),—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶,—CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃, —NO₂, —S(O)R¹⁵ and —S(O)₂R¹⁵;

or two R²¹ or two R²² moieties on adjacent carbons can be linkedtogether to form

and when R²¹ or R²² are selected from the group consisting of—C(═NOR¹⁵)R¹⁶, —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶ and —CH₂—N(R¹⁵)C(O)OR¹⁶, R¹⁵and R¹⁶ together can be a C₂ to C₄ chain wherein, optionally, one, twoor three ring carbons can be replaced by —C(O)— or —N(H)— and R¹⁵ andR¹⁶, together with the atoms to which they are attached, form a 5 to 7membered ring, optionally substituted by R²³;

R²³ is 1 to 5 groups independently selected from the group consisting ofalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CN, —OR²⁴, —C(O)R²⁴, —C(O)OR²⁴,—C(O)N(R²⁴)(R²⁵), —SR²⁴, —S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵),—C(═NOR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵), —N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵),—N(R²⁴), C(O)R²⁵, —CH₂—N(R²⁴)C(O) R²⁵, —N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵,—CH₂—N(R²⁴)S(O)₂R²⁵, —N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴; and wherein each of thealkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl andheterocycloalkenylheteroaryl groups in R²³ are independentlyunsubstituted or substituted by 1 to 5 R²⁷ groups independently selectedfrom the group consisting of alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, halo, —CF₃, —CN,—OR²⁴, —C(O)R²⁴, —C(O)OR²⁴, alkyl-C(O)OR²⁴, —C(O)N(R²⁴)(R²⁵), —SR²⁴,—S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵), —C(═NOR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵),—N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵), —N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵,—N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵, —CH₂—N(R²⁴)S(O)₂R²⁵,—N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)N(R²⁵)(R²⁶),—CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵, —CH₂—N(R²⁴)C(O)OR²⁵,—S(O)R²⁴ and —S(O)₂R²⁴;

R²⁴, R²⁵ and R²⁶ are independently selected from the group consisting ofH, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, R²⁷-alkyl, R²⁷-arylalkyl,R²⁷-heteroarylalkyl, R²⁷-cycloalkylalkyl, R²⁷-heterocycloalkylalkyl,R²⁷-arylcycloalkylalkyl, R²⁷-heteroarylcycloalkylalkyl,R²⁷-arylheterocycloalkylalkyl, R²⁷-heteroarylheterocycloalkylalkyl,R²⁷-cycloalkyl, R²⁷-arylcycloalkyl, R²⁷-heteroarylcycloalkyl,R²⁷-heterocycloalkyl, R²⁷-arylheterocycloalkyl,R²⁷-heteroarylheterocycloalkyl, R²⁷-alkenyl, R²⁷-arylalkenyl,R²⁷-cycloalkenyl, R²⁷-arylcycloalkenyl, R²⁷-heteroarylcycloalkenyl,R²⁷-heterocycloalkenyl, R²⁷-arylheterocycloalkenyl,R²⁷-heteroarylheterocycloalkenyl, R²⁷-alkynyl, R²⁷-arylalkynyl,R²⁷-aryl, R²⁷-cycloalkylaryl, R²⁷-heterocycloalkylaryl,R²⁷-cycloalkenylaryl, R²⁷-heterocycloalkenylaryl, R²⁷-heteroaryl,R²⁷-cycloalkylheteroaryl, R²⁷-heterocycloalkylheteroaryl,R²⁷-cycloalkenylheteroaryl and R²⁷-heterocycloalkenylheteroaryl;

R²⁷ is 1-5 substituents independently selected from the group consistingof alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —NO₂, halo, —CF₃, —CN, alkyl-CN, —C(O)R²⁸,—C(O)OH, —C(O)OR²⁸, —C(O)NHR²⁹, —C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl),—C(O)N(alkyl)(heteroaryl), —SR²⁸, —S(O)₂R²⁹, —S(O)NH₂, —S(O)NH(alkyl),—S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR²⁸,—S(O)₂NH(aryl), —S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OH, —OR²⁹ —O-heterocycloalkyl,—O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂, —NHR²⁹, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R²⁹, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁹, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

R²⁸ is alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl orheterocycloalkenylheteroaryl;

R²⁹ is alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl orheterocycloalkenylheteroaryl;

R³⁰ is alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl orheterocycloalkenylheteroaryl;

and

R³¹ is alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl;

with the following proviso, that when U, R^(7a) and R⁴ cyclize to formthe following bicyclic structure:

W cannot be a bond.

In another aspect, the invention relates to a pharmaceutical compositioncomprising at least one compound of formula I and a pharmaceuticallyacceptable carrier.

In another aspect, the invention comprises the method of inhibitingaspartyl proteases comprising administering at least one compound offormula I to a patient in need of such treatment.

More specifically, the invention comprises: the method of treating acardiovascular disease such as hypertension, renal failure, congestiveheart failure or another disease modulated by renin inhibition; themethod of treating Human Immunodeficiency Virus; the method of treatinga cognitive or neurodegenerative disease such as Alzheimer's Disease;the method of inhibiting plasmepsins I and II for treatment of malaria;the method of inhibiting Cathepsin D for the treatment of Alzheimer'sDisease, breast cancer, and ovarian cancer; and the method of inhibitingprotozoal enzymes, for example inhibition of plasmodium falciparnum, forthe treatment of fungal infections. Said method of treatment compriseadministering at least one compound of formula I to a patient in need ofsuch treatment. In particular, the invention comprises the method oftreating Alzheimer's Disease comprising administering at least onecompound of formula I to a patient in need of such treatment.

In another aspect, the invention comprises the method of treatingAlzheimer's Disease comprising administering to a patient in need ofsuch treatment a combination of at least one compound of formula I and acholinesterase inhibitor or a muscarinic m₁ agonist or m₂ antagonist.

In a final aspect, the invention relates to a kit comprising in separatecontainers in a single package pharmaceutical compositions for use incombination, in which one container comprises a compound of formula I ina pharmaceutically acceptable carrier and a second container comprises acholinesterase inhibitor or a muscarinic m₁ agonist or m₂ antagonist ina pharmaceutically acceptable carrier, the combined quantities being aneffective amount to treat a cognitive disease or neurodegenerativedisease such as Alzheimer's Disease.

DETAILED DESCRIPTION

In general, it is understood that divalent groups are to be read left toright.

Preferred compounds of formula I wherein R, R¹, R², R³, R⁴, R⁶, R⁷,R^(7a) and W are as defined above include the following structures:

provided that in structure II, W is not a bond.

Compounds of formula I wherein R, R¹, R², R³, R⁵, R⁶, R⁷ and W are asdefined above also include the following structures:

wherein b is 1 to 5 and c is 0 to 5.or

wherein R, R¹, R², R³, R⁵, R⁶, R⁷ and W, wherein b is 1 to 5 and c is 0to 5 or

wherein R, R¹, R², R³, R⁵, R⁶, R⁷ and W are as defined above, b is 1 to4 and c is 0 to 4.

Preferred compounds of formula I are those compounds wherein R¹ is alkylor more preferably, R¹ is methyl.

More preferred compounds of the invention are those of formula I whereinR² is H.

Another group of preferred compounds of formula I are those compoundswherein R⁶ is aryl, (R²¹)₁₋₅-aryl, heteroaryl or (R²¹)₁₋₅-heteroaryl oreven more preferably, R⁶ is

Preferred compounds of formula I are those compounds wherein R²¹ is —CN,halo, aryl, (R²²)₁₋₂-aryl, heteroaryl or (R²²)₁₋₂-heteroaryl.

Preferred compounds of formula I are those compounds wherein R²² is —CN,halo or alkyne, or more preferably, R²² is F or

Preferred compounds of formula I are those compounds wherein R²¹ is

More preferred compounds of formula I are those compounds wherein W is—C(O)—.

Another group of preferred compounds of formula I are those compoundswherein R⁴ and R^(7a) form R⁴ and R^(7a) form

Preferred compounds of formula I are those compounds wherein R is halo,more preferably where R is F.

Preferred compounds of formula I are those compounds wherein

R is H or halo;

R¹ is alkyl;

R² is H;

R⁶ is R²¹-aryl;

R²¹ is R²²-aryl;

R²² is halo or CN;

W is —C(O)—;

and

R⁴ and R^(7a) form

Another group of preferred compounds of formula I are those compoundswherein

R¹ is alkyl;

R² is H;

R⁶ is R²¹-aryl;

R²¹ is R²²-aryl;

R²² is halo or CN;

W is —C(O)—;

and

R⁴ and R^(7a) form

An even further group of preferred compounds of formula I are thosecompounds wherein

R¹ is methyl;

R² is H;

R⁶ is

R²¹ is

W is —C(O)—;

and

R⁴ and R^(7a) form

In a group of preferred compounds of formula I are those compoundshaving the structure:

wherein R is defined herein.

The following preferred compounds of formula I have the followingstructures;

An further group of preferred compounds of formula I are those compoundswhere R⁴ and R^(7a) form

A further group of preferred compounds of formula I are those compoundshaving the following structure

wherein R⁵ and R⁶ are as defined as above.

A group of preferred compounds of formula I are those compounds where R⁵is independently selected from the group consisting of arylalkyl, aryl,heteroaryl, —C(═NR¹¹)R⁸, —C(O)R⁸, —C(O)OR⁹, aryl-R²¹ and heteroaryl-R²¹,or more preferably, R⁵ is

An even further group of preferred compounds of formula I are thosecompounds where R¹⁸ is 1-5 substituents independently selected from thegroup consisting of alkyl, halo, —CF₃, —CN, —SR¹⁹ and —OR²⁰, or evenmore preferably, R¹⁸ is 1-5 substituents independently selected from thegroup consisting of halo, —CN, —OCH(CH₃)₂, —OCH₃, —CH₃,

An even further group of preferred compounds of formula I are thosecompounds wherein R²¹ is 1-5 substituents independently selected fromthe group consisting of halo, —OCH(CH₃)₂, —CH₃, —CF₃, —OCH₃, —CH(CH₃)₂and —CN.

It is noted that the carbons of formula I may be replaced with 1 to 3silicon atoms so long as all valency requirements are satisfied.

As used above, and throughout the specification, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. Non-limiting examples ofsuitable alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, n-pentyl, heptyl, nonyl and decyl. R²¹-substitutedalkyl groups include fluoromethyl, trifluoromethyl andcyclopropylmethyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkenyl groups includeethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyland decenyl.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more substituents (e.g., R¹⁸, R^(21,) R²², etc.) which may be thesame or different, and are as defined herein or two substituents onadjacent carbons can be linked together to form

Non-limiting examples of suitable aryl groups include phenyl andnaphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one to four of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more R²¹substituents which may be the same or different, and are as definedherein. The prefix aza, oxa or thia before the heteroaryl root namemeans that at least a nitrogen, oxygen or sulfur atom respectively, ispresent as a ring atom. A nitrogen atom of a heteroaryl can beoptionally oxidized to the corresponding N-oxide. Non-limiting examplesof suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl,furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl,pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 15 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore R²¹ substituents which may be the same or different, and are asdefined above. Non-limiting examples of suitable monocyclic cycloalkylsinclude cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.Non-limiting examples of suitable multicyclic cycloalkyls include1-decalin, norbornyl, adamantyl and the like. Further non-limitingexamples of cycloalkyl include the following

“Cycloalkylether” means a non-aromatic ring of 3 to 15 atoms comprisingan oxygen atom and 2 to 14 carbon atoms. Ring carbon atoms can besubstituted, provided that substituents adjacent to the ring oxygen donot include halo or substituents joined to the ring through an oxygen,nitrogen or sulfur atom.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 15 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.The cycloalkenyl ring can be optionally substituted with one or more R²¹substituents which may be the same or different, and are as definedabove. Preferred cycloalkenyl rings contain about 5 to about 7 ringatoms. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Heterocyclenyl” (or “heterocycloalkenyl”) means a non-aromaticmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur atom, alone or in combination,and which contains at least one carbon-carbon double bond orcarbon-nitrogen double bond. There are no adjacent oxygen and/or sulfuratoms present in the ring system. Preferred heterocyclenyl rings containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclenyl root name means that at least a nitrogen, oxygen orsulfur atom respectively is present as a ring atom. The heterocyclenylcan be optionally substituted by one or more ring system substituents,wherein “ring system substituent” is as defined above. The nitrogen orsulfur atom of the heterocyclenyl can be optionally oxidized to thecorresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples ofsuitable monocyclic azaheterocyclenyl groups include1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl,1,2,3,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidyl, 2-pyrrolinyl,3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Non-limitingexamples of suitable oxaheterocyclenyl groups include3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and thelike. Non-limiting example of a suitable multicyclic oxaheterocyclenylgroup is 7-oxabicyclo[2.2.1]heptenyl. Non-limiting examples of suitablemonocyclic thiaheterocyclenyl rings include dihydrothiophenyl,dihydrothiopyranyl, and the like.

“Halo” means fluoro, chloro, bromo, or iodo groups. Preferred arefluoro, chloro or bromo, and more preferred are fluoro and chloro.

“Haloalkyl” means an alkyl as defined above wherein one or more hydrogenatoms on the alkyl is replaced by a halo group defined above.

“Heterocyclyl” (or heterocycloalkyl) means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which 1-3,preferably 1 or 2 of the atoms in the ring system is an element otherthan carbon, for example nitrogen, oxygen or sulfur, alone or incombination. There are no adjacent oxygen and/or sulfur atoms present inthe ring system. Preferred heterocyclyls contain about 5 to about 6 ringatoms. The prefix aza, oxa or thia before the heterocyclyl root namemeans that at least a nitrogen, oxygen or sulfur atom respectively ispresent as a ring atom. The heterocyclyl can be optionally substitutedby one or more R²¹ substituents which may be the same or different, andare as defined herein. The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and thelike.

“Arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl areas previously described. Preferred aralkyls comprise a lower alkylgroup. Non-limiting examples of suitable aralkyl groups include benzyl,2-phenethyl and naphthalenylmethyl. The bond to the parent moiety isthrough the alkyl.

“Arylcycloalkyl” means a group derived from a fused aryl and cycloalkylas defined herein. Preferred arylcycloalkyls are those wherein aryl isphenyl and cycloalkyl consists of about 5 to about 6 ring atoms. Thearylcycloalkyl can be optionally substituted by 1-5 R²¹ substituents.Non-limiting examples of suitable arylcycloalkyls include indanyl and1,2,3,4-tetrahydronaphthyl and the like. The bond to the parent moietyis through a non-aromatic carbon atom.

“Arylheterocycloalkyl” means a group derived from a fused aryl andheterocycloalkyl as defined herein. Preferred arylcycloalkyls are thosewherein aryl is phenyl and heterocycloalkyl consists of about 5 to about6 ring atoms. The arylheterocycloalkyl can be optionally substituted by1-5 R²¹ substituents. Non-limiting examples of suitablearylheterocycloalkyls include

The bond to the parent moiety is through a non-aromatic carbon atom.

Similarly, “heteroarylalkyl” “cycloalkylalkyl” and“heterocycloalkylalkyl” mean a heteroaryl-, cycloalkyl- orheterocycloalkyl-alkyl- group in which the heteroaryl, cycloalkyl,heterocycloalkyl and alkyl are as previously described. It is alsounderstood that the terms “arylcycloalkylalkyl”,“heteroarylcycloalkylalkyl”, “arylheterocycloalkylalkyl”,“heteroarylheterocycloalkylalkyl”, “heteroarylcycloalkyl”,“heteroarylheterocycloalkyl”, “arylcycloalkenyl”,“heteroarylcycloalkenyl”, “heterocycloalkenyl”,“arylheterocycloalkenyl”, “heteroarylheterocycloalkenyl”,“cycloalkylaryl”, “heterocycloalkylaryl”, “heterocycloalkenylaryl”,“heterocycloalkylheteroaryl”, “cycloalkenylaryl”“cycloalkenylheteroaryl”, “heterocycloalkenylaryl” and“heterocycloalkenylheteroaryl” similarly represented by the combinationof the groups aryl-, cycloalkyl-, alkyl-, heteroaryl-,heterocycloalkyl-, cycloalkenyl- and heterocycloalkenyl- as previouslydescribed. Preferred groups contain a lower alkyl group. The bond to theparent moiety is through the alkyl.

“Acyl” means an H—C(O)—, alkyl-C(O)—, alkenyl-C(O)—, alkynyl-C(O)— orcycloalkyl-C(O)— group in which the various groups are as previouslydescribed. The bond to the parent moiety is through the carbonyl.Preferred acyls contain a lower alkyl. Non-limiting examples of suitableacyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl,butanoyl and cyclohexanoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.The bond to the parent moiety is through the ether oxygen.

“Alkoxyalkyl” means a group derived from an alkoxy and alkyl as definedherein. The bond to the parent moiety is through the alkyl.

“Arylalkenyl” means a group derived from aryl and alkenyl as definedherein. Preferred arylalkenyls are those wherein aryl is phenyl and thealkenyl consists of about 3 to about 6 atoms. The arylalkenyl can beoptionally substituted by one or more R²⁷ substituents. The bond to theparent moiety is through a non-aromatic carbon atom.

“Arylalkynyl” means a group derived from aryl and alkynyl as definedherein. Preferred arylalkynyls are those wherein aryl is phenyl and thealkynyl consists of about 3 to about 6 atoms. The arylalkynyl can beoptionally substituted by one or more R²⁷ substituents. The bond to theparent moiety is through a non-aromatic carbon atom.

The suffix “ene” on alkyl, aryl, hetercycloalkyl, etc. indicates adivalent moiety, e.g., —CH₂CH₂— is ethylene, and

is para-phenylene.

It is understood that multicyclic divalent groups, for example,arylheterocycloalkylene, can be attached to other groups via bonds thatare formed on either ring of said group. For example,

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties, in available position orpositions.

Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, orheteroarylalkyl moiety includes substitution on the ring portion and/oron the alkyl portion of the group.

When a variable appears more than once in a group, e.g., R⁸ in—N═C(R⁸)₂, or a variable appears more than once in the structure offormula I, e.g., R¹⁵ may appear in both R¹ and R³, the variables can bethe same or different.

With reference to the number of moieties (e.g., substituents, groups orrings) in a compound, unless otherwise defined, the phrases “one ormore” and “at least one” mean that there can be as many moieties aschemically permitted, and the determination of the maximum number ofsuch moieties is well within the knowledge of those skilled in the art.With respect to the compositions and methods comprising the use of “atleast one compound of formula I,” one to three compounds of formula Ican be administered at the same time, preferably one.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The wavy line

as a bond generally indicates a mixture of, or either of, the possibleisomers, e.g., containing (R)- and (S)-stereochemistry. For example,

means containing both

Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of thesubstitutable ring carbon atoms.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

represents

It should also be noted that any heteroatom with unsatisfied valences inthe text, schemes, examples, structural formulae, and any Tables hereinis assumed to have the hydrogen atom or atoms to satisfy the valences.Those skilled in the art will recognize that certain compounds offormula I are tautomeric, and all such tautomeric forms are contemplatedherein as part of the present invention. For example, a compound whereinR¹ is H, said compound can be represented by any of the followingstructures:

When, R⁸, for example is, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), and R¹⁶ and R¹⁷ forma ring, the moiety formed, is, for example

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a compound of Formula(I) or a pharmaceutically acceptable salt, hydrate or solvate of thecompound. The transformation may occur by various mechanisms (e.g., bymetabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a compound of Formula (I) or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C1-C2)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula (I) contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N-(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula (I) incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N- ordi-N,N-(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N- or di-N,N-(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting aspartyl protease and/or inhibiting BACE-1 andthus producing the desired therapeutic effect in a suitable patient.

The compounds of formula I form salts which are also within the scope ofthis invention. Reference to a compound of formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the formula I may be formed, for example, by reacting a compound offormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization. Acids (and bases) which are generallyconsidered suitable for the formation of pharmaceutically useful saltsfrom basic (or acidic) pharmaceutical compounds are discussed, forexample, by S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website); and P. HeinrichStahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts:Properties, Selection, and Use, (2002) Int'l. Union of Pure and AppliedChemistry, pp. 330-331. These disclosures are incorporated herein byreference thereto.

Exemplary acid addition salts include acetates, adipates, alginates,ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates,borates, butyrates, citrates, camphorates, camphorsulfonates,cyclopentanepropionates, digluconates, dodecylsulfates,ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides,hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates,methanesulfonates, methyl sulfates, 2-naphthalenesulfonates,nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates,3-phenylpropionates, phosphates, picrates, pivalates, propionates,salicylates, succinates, bisulfates, sulfates, sulfonates (such as thosementioned herein), tartarates, thiocyanates, toluenesulfonates (alsoknown as tosylates), undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, aluminum salts, zinc salts, salts withorganic bases (for example, organic amines) such as benzathines,diethylamine, dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, piperazine,phenylcyclohexylamine, choline, tromethamine, and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quarternized with agents such as lower alkyl halides (e.g.methyl, ethyl, propyl, and butyl chlorides, bromides and iodides),dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates),long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g. benzyl and phenethylbromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates and prodrugs of the compounds as well as the salts and solvatesof the prodrugs), such as those which may exist due to asymmetriccarbons on various substituents, including enantiomeric forms (which mayexist even in the absence of asymmetric carbons), rotameric forms,atropisomers, and diastereomeric forms, are contemplated within thescope of this invention. Individual stereoisomers of the compounds ofthe invention may, for example, be substantially free of other isomers,or may be admixed, for example, as racemates or with all other, or otherselected, stereoisomers. The chiral centers of the present invention canhave the S or R configuration as defined by the IUPAC 1974Recommendations. The use of the terms “salt”, “solvate”, “prodrug” andthe like, is intended to equally apply to the salt, solvate and prodrugof enantiomers, stereoisomers, rotamers, tautomers, racemates orprodrugs of the inventive compounds.

Polymorphic forms of the compounds of formula I, and of the salts,solvates and prodrugs of the compounds of formula I, are intended to beincluded in the present invention

Compounds of formula I can be made using procedures known in the art.The following reaction schemes show typical procedures, but thoseskilled in the art will recognize that other procedures can also besuitable.

In the Schemes and in the Example below, the following abbreviations areused:

room temperature: r.t.

high pressure liquid chromatography: HPLC

reverse-phase HPLC: RP-HPLC

liquid chromatography mass spectrometry: LCMS

mass spectrometry: MS

polytetrafluoroethylene: PTFE

hour: h

minute: min

retention time: tR

ethyl: Et

methyl: Me

benzyl: Bn

lithium diisopropylamide: LDA

1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride: EDCI

DIEA means N,N-diisopropylethylamine

ethyl acetate: EtOAc

N,N-dimethylformamide: DMF

methanol: MeOH

Ethanol: EtOH

acetonitrile: CH₃CN

acetic acid: AcOH

magnesium sulfate: MgSO₄

copper iodide: Cul

diisopropylamine: iPr₂NH

Dichlorobis(triphenylphosphine)palladium: PdCl₂(PPh₃)₂

ammonium hydroxide: NH₄OH

trifluoroacetic acid: TFA

benzyloxycarbonyl: Cbz

tert-butoxycarbonyl: Boc

DCM: Dichloromethane

TMSCHN₂: Trimethylsilyidiazomethane

Teoc-OSu: O-Trimethylsilylethoxycarbonyl N-hydroxylsuccinate

TBAF: Tetrabutylammonium Flouride

THF: Tetrahydrofurane

MCPBA: meta-Chloroperbenzoic acid

TsOH: Toluenesulfonic acid.

PhlO: iodosobenzene

Pb(OAc)₄: Lead tetra-acetate

Method A, Step 1

A literature procedure is adapted (Y. Kazuta, et. al. Bioorganic &Medicinal Chemistry, 10 (2002), 3829-3848). Thus, to a suspension ofNaNH₂ (22.0 mmol) in benzene (20 mL) is added a solution of3-bromophenylacetonitrile (10 mmol) in benzene (10 ml) at 0° C., and thereaction is stirred at r.t. for 2 h. After the solvent is evaporated theresidue is chromatographed to give product A3.

Method A, Step 2

A similar literature procedure is adapted (Casadio, S. et. al.Bollettino Chimico Farmaceutico (1978), 117(6), 331-42). Compound A3 isdissolved in 7N NH₃/MeOH and the solution is heated in a sealed tube to70 0° C. for 1 h. before the solvent is evaporated. The result amide (10mmol) redissolved in MeOH is treated with aq NaOBr (5 eq) overnightbefore the reaction mixture is partitioned between DCM/water. Theorganic layer is washed with brine and dried with Na₂SO₄ and evaporatedto give the crude cyclic carbamate which is hydrolyzed with Ba(OH)₂ indioxane/water under heat overnight to give the aminoalcohol. Thesolution is cooled to r.t. and its pH is adjusted to 9 using aq NaHSO₄before TEOC-OSu (1.1 eq) is added. The reaction is stirred for 5 hbefore the solution is partitioned between DCM/water. The organicsolution is washed with brine and dried over Na₂SO₄ and subsequentlyevaporated to give crude product which is purified via a silica gelcolumn to compound A4.

Method A, Step 3,

A literature procedure is adapted (Tetrahedron Letters 2003). To amixture of A4 in CCl₄/Acetonitrile/H₂O (5/5/1) is added RuCl₃ (0.1 eq),NaIO₄ (10 eq) and NaHCO₃ (10 eq) and the reaction is stirred overnightbefore the mixture is acidified to pH 3 and partitioned in DCM/water.The organic layer is dried and solvent evaporated to give the amino acidproduct which is dissolved in MeOH and treated with TMSCHN₂ to give thecorresponding amino ester after evaporation of the solvent. The aminoester is treated with 1 N TBAF in THF for 20 min before the reactionmixture is diluted with Ether and filtered through a silica gel pad togive the amino ester product A5.

Method A, Step 4,

To a DMF solution of A5 is added N-methyl-N′-Boc-thiourea (1 eq)followed by addition of EDCI (1 eq) and DIEA (2 eq) and the solution isstirred overnight. The solvent is evaporated under vacuum and residuechromatographed to give the boc-ed iminopyrimidinone A6.

Method A, Step 5.

A mixture of compound A6, 3-cyanophenylboronic acid, Fibrecat (4.26% ofPd, 0.7 g) and 1 N aq. K₂CO₃ (0.5 mL) in tert-butanol (10 mL) is heatedat 110° C. for 15 min. After cooling, the reaction mixture istransferred to a pre-packed Si-Carbonate column and eluted withMeOH/CH₂Cl₂ (1:1). The eluant is collected and concentrated underreduced pressure to give a crude product which is purified by silica gelchromatography (20-50% EtOAc/hexanes gradient) to yield the product.After treatment of the product with 30% TFA in DCM for 20 min followedby evaporation of solvent, product A7 is obtained.

Method B, Step 1:

A literature procedure is adapted (Bernard, A. et. al Tetrahedron(2004), 60(2), 449-457). Compound B1 (1 g) and B2 (1.1 eq) in anhydrousTHF is treated with NaH (1.5 eq) and the mixture is stirred at r.t.overnight. After evaporation of solvent the residue is purified viasilica gel column to give compound B3.

Method B, Step 2:

A mixture of compound B3 (1 g), MCPBA (2 eq) and NaHCO₃ (5 eq) isstirred overnight before it is diluted with DCM and washed with aqNaHCO₃, brine and dried. The solvent is evaporated to give a crudeepoxide. This crude product is dissolved in anhydrous benzene and 100 mgof p-toluenesulfonic acid is added. The reaction is refluxed overnightbefore it is cooled to r.t., washed with aq NaHCO₃ and concentrated togive product B4.

Method B, Step 3;

A solution of B4 (1 g) in 20% TFA in DCM is treated with triethylsilane(3 eq) or with NaBH₄. After removal of the volatiles, the residue ischromatographed to give a product which is dissolved in a mixture ofCCl₄/Acetonitrile/water (5/5/1) and RuCl₃ (0.1 eq)/NaIO₄ (10 eq). Thereaction mixture is stirred over night before the solid is filtered andthe liquid mixture is concentrated. The residue is stirred with 10 mlacetic anhydride for 30 min before the volatile is evaporated to give acrude product B5.

Method B, Step 4.

The crude product anhydride is redissolved in MeOH. The reaction isrefluxed for 1 h and solvent evaporated. The residue is redissolved inDMF followed by addition of NH₄Cl (5 eq) and EDCI hydrochloric salt (1.5eq) and DIEA (5 eq). The reaction mixture is stirred overnight before itis partitioned in DCM/Water. The organic layer is dried, solventevaporated and the residue is chromatographed to give the primary amideB6.

Method B, Step 5.

To a solution of B6 in acetonitrile/water/formic acid (3/1/6) is addedPhIO (2 eq) and the mixture is stirred overnight before said mixture ismade basic (pH 10) using aq Na₂CO₃ and partitioned between DCM andwater. The organic layer is dried and solvent evaporated. The residue isredissolved in DMF and EDCI (1.1 eq), N-methyl-N′-Boc-thiourea (1.1 eq)and DIEA (2 eq) is added. The reaction is stirred overnight before it ispartitioned between DCM and water. The organic layer is washed withbrine and dried over Na₂SO₄ and solvent evaporated. The residue ispurified with a silica gel column to give product B7.

Method B, Step 6

Product B8 is obtained using method similar to Method A step 5.

Method C, Step 1.

A literature procedure is adapted (JOC, 1993, (58), 7916). To a solutionof 36 g of m-bromophenylacetonitrile and glyoxaldehyde (44.4 m 150% aqsolution) in 350 ml of MeOH is added 63 g (2.5 eq) of K₂CO₃ and thereaction mixture is stirred at r.t. for 4 h. The solid is filtered andwashed with ether before it is resuspended in cold water and stirredvigorously for 1 h. The white solid is filtered to give crude productC2.

Method C, Step 2;

The crude product C2 (50 g) is dissolved in 400 ml of formic acid and 40ml conc. sulfuric acid and the solution is refluxed overnight. After thereaction is cooled down, the mixture is poured into ice water and thesolid filtered to give product C3.

Method C, Step 3;

To a solution of C3 (0.27 g) and C4 (1.0 eq) in 3 ml of anhydrous DCM isadded 0.5 of TFA and the solution is stirred at r.t. overnight. Afterremoval of solvent, the residue is purified using a reverse phase C-18column to give product C5.

Method C, Step 4.

Compound C6 is obtained using a procedure similar to Method B, step 5

Method C. Step 5.

Product C7 is obtained using procedure similar to Method A step 4,5.

Method C, Step 6

Compound C8 is obtained through debenzylation of C7 under Pdhydrogenation conditions.

Method C, Step 7,8,9

Conventional amide, sulfonamide and urea formation conditions are usedfor compound C9, C10 and C11.

Method D, Step 1

A literature procedure is used for generation of compound D2 and D3(Gwaltney, S. et. al Bioorganic & Medicinal Chemistry Letters (2003),13(7), 1359-1362). 3-m-bromophenylisonicotinic acid methyl ester (D1) istreated with BnBr in DCM for 3 h at 50° C. before it is cooled to r.t.and NaBH₃CN (6 eq) is added. The reaction is stirred overnight before itis diluted with DCM and washed with water and brine. The residue afterremoval of organic solvent is purified via a silica gel column to affordD2.

Method D, Step 2.

Compound D2 is treated with 1-Chloroethylchloroformate in DCM for 2 h atr.t. before it is quenched with MeOH. After dilution with DCM, thereaction mixture is washed with aq Na₂CO₃. The organic layer is driedand solvent evaporated to give a crude product which is treated withTrifluroacetic anhydride (2 eq) and TEA (2 ea) in DCM. The reaction isstirred for 1 h before it is quenched with water and the DCM solution isdried and concentrated to give compound D3 after purification.

Method D, Step 3

A literature procedure is adapted (Selective aziridination of olefinicesters. Deshmukh, M.; Chavan, P.; Kharade, D Monatshefte fuer Chemie(1994), 125(6-7), 743-6). To a DCM solution of D3 and D4 (1.2 eq) isadded Lead tetraacetate (2 eq) and the reaction is stirred overnightbefore it is diluted with DCM and washed with aq NaHCO₃, brine. The DCMlayer is dried and solvent evaporated. The residue is chromatographed togive compound D5.

Method D, Step 4

A literature procedure is adapted (Atkinson, R et. al. TetrahedronLetters (2002), 43(11), 2083-2085). To a THF solution of D5 is addedSmI2 in THF (4 eq) before the reaction is quenched with water andreaction is adjusted to pH 9. The reaction mixture is partitionedbetween DCM and water. The organic solution is dried and solventevaporated to give crude product D6.

Method D, Step 5.

Product D7 is obtained using a procedure similar to Method A Step 4followed by Method Step 5 for the Suzuki coupling.

Method D, Step 6,

Compound D8 is obtained by treatment of D7 with 2N ammonia in MeOH.

Method D, Step 7, 8 and 9

Conventional amide, sulfonamide and urea formation procedures are usedfor generation of D9, D10 and D11 after TFA deprotection of the Bocgroup.

Method E, Step 1.

To a solution of aldehyde E1 (R⁶=4-Bromothien-2-yl, 20 g) in 100 mLmethanol was added 4 g of NaBH₄ at 0° C. and the resulting solution wasstirred until the reaction was completed at 0° C. To the reaction wasquenched with water (100 mL) before the solvent was evaporated. Theresidue was extracted with ethyl acetate/water, and the organic layerswere combined and washed with brine, dried with MgSO₄, evaporated toprovide a alcohol which was used without further purification.

NMR(H¹, CDCl₃) of product alcohol (R⁶=4-Bromothien-2-yl): δ 7.17, s, 1H;6.93 s, 1H; 4.80, d (J=6.0 Hz), 2H; 1.84, t (J=6.0 Hz), 1H.

To a solution of the above alcohol in 10 mL CH₂Cl₂ was added 1.2 equiv.of SOCl₂ at 0° C. The resulting reaction mixture was stirred at 0° C.for 30 min and at rt for 2 h. The reaction mixture was extracted withethyl acetate/water and the organic layers were washed with brine, driedwith MgSO4 and evaporated to yield a chloride.

NMR(H¹, CDCl₃) of product chloride (R⁶=4-Bromothien-2-yl): δ 7.15-7.30,m, 2H; 4.73, s, 2H.

To the chloride (4.4 g, 21 mmol) in 50 mL of AcCN was added KCN (3.6equiv, 5 gm, 76 mmol) and the resulting reaction mixture was stirred atrt for 1 hr before it was heated under reflux until the disappearance ofstarting. The reaction mixture was diluted with ethyl acetate, filteredand the solid was washed with ethyl acetate. The combined filtrate waswashed with water, brine, dried and concentrated. The residue waschromatographed using ethyl acetate/hexane to give product E2(R⁶=4-Bromothien-2-yl, 75%).

NMR (H¹, CDCl₃) of E2 (R⁶=4-Bromothien-2-yl): δ 7.18, s, 1H; 7.00, s,1H, 3.89, s, 2H.

Method E, Step 2;

A literature procedure was adapted (JOC, 1993, (58), 7916). To asolution of 4 g of E2 (R⁶=4-Bromothien-2-yl) and glyoxaldehyde (1.5 eq,50% aq solution) in 50 ml of MeOH was added 6.9 g (2.5 eq) of K₂CO₃ andthe reaction mixture was stirred at r.t. for 4 h. The solid was filteredand washed with ether before it was resuspended in cold water andstirred vigorously for 1 h. The white solid is filtered and dried togive crude product E3 (R⁶=4-Bromothien-2-yl) which was used withoutfurther purification. A small quantity of E3 was extracted with EtOAc/1NHCl and the organic solution was evaporated to give the correspondingfree acid of E3 (R⁶=4-Bromothien-2-yl).

NMR(H¹, CDCl₃) of E3 (R⁶=4-Bromothien-2-yl) as a free acid: δ 7.69, s,1H; 7.56, s, 1H; 6.96, s, 1H.

Method E, Step 3;

The crude product E3 (R⁶=4-Bromothien-2-yl) (50 g) was dissolved in 400ml of formic acid and 40 ml conc. sulfuric acid. The solution wasrefluxed for 2 h. before it was cooled down to rt. The solution waspoured into ice water and the solid filtered to give product E4(R⁶=4-Bromothien-2-yl) (80%).

NMR(H¹, CDCl₃) of E4 (R⁶=4-Bromothien-2-yl): δ 7.88, s, 1H; 7.84, s, 1H;7.09, s, 1H.

Method E, Step 4;

A solution of E4 (R⁶=4-Bromothien-2-yl) (27 g) in 300 ml mixture ofacetonitril and water (10%) was heated at 40° C. until the startingmaterial disappeared. The reaction solution was concentrated and theresidue dried in vaccuo to give compound E5 (R⁶=4-Bromothien-2-yl) inquantitative yield.

NMR(H¹, CDCl₃) of E4 (R⁶=4-Bromothien-2-yl): δ 7.66, s, 1H; 7.40, s, 1H;6.42, s, 1H.

Method E, Step 5.

To solution of E5 (R⁶=4-Bromothien-2-yl) (5 g, 18.17 mmol) in 72 mLanhydrous THF was added E4 (2.0 equiv. 6 mL) at 0° C. and the resultingsolution was stirred at 0° C. for 90 min. before the reaction wasquenched with 10 mL 1N HCl at 0° C. and the reaction mixture wasextracted with ethyl acetate and the organic layers were combined, driedwith anhydrous Na₂SO₄, then concentrated to yield 6 g of E6(R⁶=4-Bromothien-2-yl), which was used for next step without furtherpurification.

NMR(H¹, CD₃O D) of E6 (R⁶=4-Bromothien-2-yl): δ 7.45-7.60, m, 7H; 4.49,m, 2H; 4.30, d (J=12 Hz), 1H; 3.8-4.0, m, 4H.

Method E, Step 6.

To a oven-dried flask containing E6 (R⁶=4-Bromothien-2-yl) (6 g) wasadded acetic anhydride (100 mL) at rt. The resulting solution was heatedfor 30 min at 90° C. before the reaction mixture was cooled to rt,poured into a flask containing 500 mL methanol at 0° C. and the solutionwas evaporated to dryness. The crude product was dissolved in 200 mLCH₂Cl₂, washed with 1H HCl, brine, dried with Na₂SO₄ and concentrated toobtain 6 g of product E7 (R⁶=4-Bromothien-2-yl) as a HCl salt (yield96%) which was taken for next step without purification.

NMR(H¹, CDCl₃) of E7 (R⁶=4-Bromothien-2-yl): δ 7.10-7.60, m, 7H; 4.3, m,2H; 4.12, d (J=12 Hz), 1H; 3.7-3.9, m, 4H; 3.6, s, 3H.

Method E. Step 7.

To an oven-dried flask containing Compound E7 (R⁶=4-Bromothien-2-yl)(4.67 gm) in 10 mL toluene was added DPPA (2 equiv, 14.18 mmol, 3 mL)followed by triethyl amine (2.2 equiv, 2.16 mL) at 0° C. before themixture was stirred at rt overnight. To the reaction mixture was addedtrimethylsilylethanol (4 equiv. 4 mL) and the reaction mixture wasrefluxed for 1 hr before it was cooled to rt, diluted with ethyl acetate(150 mL), washed with brine, water, dried with Na₂SO₄ and concentrated.The crude product was chromatographed using a silica gel column elutedwith (30% ethyl acetate in hexanes) to obtain 1.5 g of E8(R⁶=4-Bromothien-2-yl) (40%)

NMR(H¹, CDCl₃) of E8 (R⁶=4-Bromothien-2-yl): δ 7.20-7.40, m, 5H; 7.07, d(J=1.5 Hz), 1H; 6.94, d (J=1.5 Hz), 1H; 4.11, m, 2H; 3.79, AB (J=11 Hz),1H; 3.70, s, 3H; 3.69, AB (J=11 Hz), 1H; 3.54, AB (J=10 Hz), 1H; 3.32, t(J=8 Hz), 1 H; 3.21, AB (J=10 Hz), 1H; 3.16, t (J=8 Hz), 1H; 2.88, t(J=8 Hz), 1H; 0.97, m, 2H; 0.03, s, 9H.

Method E. Step 8.

To a solution of 35.2 g of E8 (R⁶=4-Bromothien-2-yl) in 200 ml dioxanewas added 20 ml of 4N HCl in dioxane at 0 C and the solution was allowedto warm to rt over 14 h before ether (400 ml) was added. The whiteprecipitate was collected and washed with 200 ml of ether, dried in avacuum oven overnight to give 36.7 g of a HCl salt, which was usedwithout further purification.

NMR(H¹, CDCl₃) of the product amine HCl salt (R⁶=4-Bromothien-2-yl): δ7.17, d (J=1.5 Hz), 1H; 6.86, d (J=6.86 Hz), 1H; 3.65-2.71, m, 1H;3.45-3.31, m, 6H; 3.29, s, 3H.

To a DMF solution (300 ml) of the HCl salt (76 mmol) was added DIEA (5eq), and N-methyl-N′-Boc-thiourea (1 eq) followed by addition ofEDCI.HCl (1.05 eq) and the solution was stirred at rt for 48 h before itwas extracted with EtOAc/water. After removal of organic solvent, theresidue was chromatographed via a silica gel column to give product E11(R⁶=4-thien-2-yl, R¹=Me).

NMR(H¹, CDCl₃) for E11 (R⁶=4-thien-2-yl, R¹=Me): δ 7.25-7.34, m, 5 H;7.15, d (J=1.5 Hz), 1H; 6.91, d (J=1.5 Hz), 1H; 3.75, m, 2H; 3.42, m,1H; 3.34, m, 1H; 3.31, S, 3H; 3.22, AB (J=10 Hz), 1H; 3.09, AB (J=10Hz), 1H; 3.02, M, 1H; 1.54, S, 9H.

Method E. Step 9

To a mixture of DCM solution (10 ml) of E11 (R⁶=4-thien-2-yl, R¹=Me; 1g) and potassium carbonate (300 mg) was added 1-chloroethylchloroformateat −15° C. and the solution was stirred for 1.5 h at r.t. before themixture was filtered followed by evaporation of the solvent. The residuewas redissolved in 10 ml methanol and the reaction left overnight. Afterremoval of methanol in vaccuo, the residue was chromatographed to giveE12 as a solid (R⁶=4-thien-2-yl, R¹=Me; 70% yield).

NMR(H¹, CDCl₃) for E12 (R⁶=4-thien-2-yl, R¹=Me): δ 10.30, br, s, 1H;7.17, d (J=1.5 Hz), 1H; 6.86, d (J=1.5 Hz), 1H; 3.68, m, 1H; 3.42,d(J=12 Hz), 1H, 3.31-3.40, m, 3H, 3.29, s, 3H; 1.52, s, 9H.

Method E. Step 10

To a solution of 13 g of E12 (R⁶=4-thien-2-yl, R¹=Me) in 100 ml DCM wasadded Teoc-OSu (1.03 eq) and DIEA (1.1 eq) at 0° C. The reaction wasstirred until disappearance of E12 (R⁶=4-thien-2-yl, R¹=Me) before itwas extracted with EtOAc/water. The organic layer was dried and solventevaporated and the residue chromatographed to give E13 (R⁶=4-thien-2-yl,R¹=Me) as an oil.

NMR(H¹, CDCl₃) for E13 (R⁶=4-thien-2-yl, R¹=Me): δ 10.40, br, m, 1H;7.22, br. s, 1H; 6.90, 1H; 4.20, m, 2H; 3.68-4.06, m, 4H; 3.47, m, 1H;3.30, s, 3H; 1.29, s, 9H; 1.01, m, 2H; 0.03, s, 9H.

E13 (R⁶=4-thien-2-yl, R¹=Me) was resolved using a semi-prep ChiralPak AScolumn eluted with 50% isopropanol in hexane (50 ml/min): t=19.3 min,enantiomer I, E19 (R⁶=4-thien-2-yl, R¹=Me), [D]=−94° mL g⁻¹ dm⁻¹ (MeOH,C=1, 23° C.); t=39.5 min, enantiomer II, E20 (R⁶=4-thien-2-yl, R¹=Me),[D]=+105° mL g⁻¹ dm⁻¹ (MeOH, C=1, 23° C.).

The following compounds were produced using similar methods:

The following compounds were generated using method similar to Method Efollowed by deprotection of Boc using 20% TFA in DCM.

Obs. Obs. Structure Mass Structure Mass

463.25

385.21

341.19

385.21

385.21

Method F, Step 1

A MeOH solution (40 ml) of E17 (1.8 g, R¹=Me) was hydrogenated at 1 atmwith 0.9 g of 10% Pd/C for 1.5 h. After the solution was adjusted tobasic using Et₃N, it was filtered, concentrated and residuechromatographed to give F2 (1.41 g, R¹=Me).

NMR(H¹, CDCl₃) for F2 (R¹=Me): δ 10.40, br, m, 1H; 7.31, br. m, 1H;6.97-6.99, m, 2H; 4.20, m, 2H; 3.68-4.06, m, 4H; 3.50, m, 1H; 3.30, s,3H; 1.53, s, 9H; 1.01, m, 2H; 0.03, s, 9H.

Method F, Step 2

A DMF solution (15 ml) of F2 (1.41 g, R¹=Me) was treated with NBS (1.2eq) and the reaction was stirred overnight before it was extracted usingEtOAc/water. The organic solution was evaporated and the residuechromatographed to give F3 (R¹=Me).

NMR(H¹, CDCl₃) for F3 (R¹=Me): δ 10.39, br, m, 1H; 6.94, d (J=4 Hz), 1H;6.76, m, 1H; 4.20, m, 2H; 3.68-4.04, m, 4H; 3.43, m, 1H; 3.29, s, 3H;1.53, s, 9H; 1.01, m, 2H; 0.03, s, 9H.

Method G, Step 1;

A mixture of G1 (2.5 g), Cul (0.3 eq), palladiumtetrakistriphenylphosphine (0.05 eq), TBAF (1 N in THF, 1 eq),TMS-propyne (1 eq) and triethylamine (3.3 eq) in 400 mL of toluene wasstirred at rt for 3 h before it was extracted with DCM and water. Theorganic layer was dried, evaporated and the residue chromatographed togive compound G2 in 68% yield.

NMR(H¹, CDCl₃) for G2: δ 8.54, m, 1H; 8.51, m, 1H; 7.81, m, 1H; 2.08, s,3H.

Method G. Step 2;

To A 1000 mL flame dried flask charged with anhydrous toluene (1.6mL/mmol, 188 mL) and anhydrous THF (0.4 mL/mmol 47 mL) under nitrogenwas added triisopropyl borate (32 mL, 141.36 mmol, 1.2 equiv.) and3-bromo-3-propynylpyridine (23 gm, 117.8 mmol). The mixture was cooledto −40° C. followed by addition of n-Butyllithium (2.5 M in hexanes, 56mL, 141.36 mmol) via a syringe pump over 1 hr. The mixture was stirredfor an additional 0.5 hr while the temperature was held at −40° C.before it was warmed to −20° C. followed by addition of 2 N aq. HCl (120mL). After removal of the organic layer, the pH of the aqueous phase wasadjusted to pH7 using a 5 N NaOH solution. A white solid productprecipitated as the pH approached 7. The aq. mixture was then saturatedwith NaCl using solid NaCl, and extracted three times with THF (150 mL).The combined THF extracts were evaporated in vacuo to provide a solid,(18 gm, 95% yield).

NMR(H¹, CDCl₃) for G3: δ 8.67, s, 1H; 8.48, s, 1H; 8.09, s, 1H; 2.06, s,3H.

Method H, Step 1,

To a solution of bromide E11 (1 g, 1.74 mmol, R¹=Me) and boronic acid G3(1.5 eq, R²¹=m-propynylpyridin-3-yl) in 7 mL tBuOH was addeddichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II)dichloromethane (0.15 eq) followed by aqueous K₂CO₃ (1N, 1.5 equiv.).The resulting mixture was heated at 60° C. for 1 h before it was cooled,diluted with ethyl acetate and washed with water. The organic layer wasdried, concentrated and the residue was chromatographed using a silicagel column eluted with ethyl acetate in hexanes to give H1 (R¹=Me,R²¹=m-propynylpyridin-3-yl; Yield 90%).

NMR(H¹, CDCl₃) for H1 (R¹=Me, R²¹=m-propynylpyridin-3-yl): δ 10.45, br.1H; 8.63, br. s, 1H; 8.53, br. s, 1H; 7.76, br s, 1H; 7.46, br s, 1H;7.20, m, 1H; 4.20, m, 2H; 3.90-4.13, m, 3H; 3.74, m, 1H; 3.73, m, 1H;3.31, s, 3H; 2.08, s, 3H; 1.53, s, 9H; 1.01, m, 2H; 0.03, s, 9H.

Method H, Step 2,

Into a 25 mL flask containing H1 (1 gm, 1.64 mmol, R¹=Me,R²¹=m-propynylpyridin-3-yl) was added 5 mL of 1 M TBAF in THF at 0° C.and the solution was stirred at rt for 4 h. The reaction mixture waspoured into saturated solution of NaHCO₃, extracted with ethyl acetate.The organic layer was concentrated and residue purified with 2%MeOH/CH₂Cl₂ to give H2 (R¹=Me, R²¹=m-propynylpyridin-3-yl) in 70% yield.

NMR(H¹, CDCl₃) for H2 (R¹=Me, R²¹=m-propynylpyridin-3-yl): 810.36, s,1H; 8.65, s, 1H; 8.53, s, 1H; 7.77, s, 1H; 7.43, br s, 1H; 7.18, m, 1H;3.73, m, 1H; 3.49, m, 2H; 3.40, m, 2H; 3.32, s, 3H; 2.09, s, 3H; 1.54,s, 9H.

The following compounds were generated using similar method:

The following compounds were generated using method similar to method Hfollowing by deprotection of Boc using 20% TFA in DCM.

Obs. Obs. Structure Mass Structure Mass

504.3

467.3

511.3

NA

511.3

377.2

Method I, Step A:

To a DCM (2 ml) solution of I1 (35 mg) was added HOBt (15 mg),m-Fluorobenzoic acid (15.8 mg), DIEA (28 mg) followed by EDCI (21.5 mg)and the solution was stirred for 3 h. before it was extracted withEtOAc. The organic layer was dried, concentrated and residuechromatographed to give a product which was deprotected with 20% TFA/DCMto give product I1 after reverse phase purification.

NMR(H¹, CDCl₃) for H2 (R=m-F-benzoyl, R¹=Me,R²¹=m-propynylpyridin-3-yl): δ10.71, br s, 1H; 8.85, s, 1H; 8.58, s, 1H;8.20, s, 1H; 7.01-7.66, m, 6H; 3.80-4.45, m, 5H; 3.38, s, 3H; 2.13, s,3H.

The following compounds were generated using similar method:

Obs. Obs. Structure Mass Structure Mass

355.2

436.2

373.2

361.2

345.2

373.2

345.2

373.2

356.2

356.2

361.2

356.2

361.2

381.2

369.2

492.3

380.2

500.3

380.2

480.3

383.2

507.3

385.2

487.3

385.2

499.3

385.2

500.3

394.2

492.3

394.2

476.3

395.2

496.3

401.2

488.3

411.2

482.3

436.2

488.3

293.2

456.3

470.3

474.3

506.3

To a DCM solution (2 ml) of H2 (25 mg, R²¹=m-propynylpyridin-3-yl,R¹=Me), p-F-phenylboronic acid (20 mg), Cu(OAc)₂, and 0.1 mltriethylamine was added preactivated 4 Å molecular sieves (5 micron, 20mg). The reaction was stirred for 48 h before the solid was filtered andthe organic solution concentrated and the residue chromatographed togive a product which was deprotected using 20% TFA/DCM to give J1(R²¹=m-propynylpyridin-3-yl, R¹=Me and R=p-fluorophenyl) after reversephase purification.

The following compounds were generated using similar method: Obs. Obs.Structure Mass Structure Mass

341.2

446.2

327.2

464.3

328.2

464.3

460.3

446.3

460.3

500.3Method K, Step 1.

To a solution of K1 (3.5 g) in 60 ml 1:1 ration of DCM/HOAc was added1.5 g of NBS at 0° C. and the solution was allowed to warm-up to rt. Thereaction mixture was pured into a mixture of DCM and sat. K2CO3/Na2SO3(1:1) and the organic layer was concentrated, residue chromatographed togive K2 (100 mg) and K3 (750 mg).

Obs. Structure Mass

354.2

To a solution of bromide L1 (500 mg, 0.872 mmol, 1.0 equiv.) and boronicester (300 mg, 1.30 mmol, 1.5 equiv.) in 3 mL tBuOH were addedTris-(dibenzylideneacetone)dipalladium (0) (119 mg, 0.130 mmol, 0.15equiv.) and Tri-t-butylphosphonium tetrafluoroborate (119 mg) followedby aqueous K₂CO₃ (1M, 1.30 mL, 1.30 mmol, 1.5 equiv.). The resultingmixture was heated at 60° C. for 1 hr and TLC indicated completion ofreaction. The reaction mixture was diluted with ethyl acetate and washwith water. The organic layer was dried with MgSO4, concentrated andpurified via a silica gel column with ethyl acetate in hexanes.

NMR(H¹, CDCl₃) for L3: δ10.71, m, 1H; 8.96, s, 1H; 8.80, s, 1H; 8.40, s,1H; 7.56, s, 1H; 7.24, s, 1H; 4.17-4.22, m, 2H; 3.87-4.11, m, 3H;3.71-3.80, m, 1H; 3.50-3.60, m, 1H; 3.30, s, 3H; 1.52, s, 9H; 0.98-1.05,m, 2H; 0.07, s, 9H.

To a solution of amine M1 (15 mg, 0.033 mmol, 1.0 equiv.) and bromide M2(5 equiv.) in 0.250 mL toluene were addedTris(dibenzylideneacetone)dipalladium (0) (3.0 mg, 0.0032 mmol, 0.10equiv.) and racemic-2,2′-Bis-(diphenylphosphino)-1.1′-binaphthyl (3.0mg) followed by 12 mg of NaOtBu. The resulting mixture was heated at 70°C. for 12 hr and the crude product was purified via a silica gel columneluted with EtOAc/Hexane to give a product which was treated with 20%TFA in DCM followed by reverse phase HPLC purification to give productM3.

NMR(H¹, CD₃OD) for M3: δ7.57-8.04, m, 8H; 7.00-7.04, m, 1H; 4.32-4.56,m, 4H; 4.12-4.17, m, 1H; 3.35, s, 3H; 2.55, s, 3H.

The following compounds were generated using method similar to Method M.

Obs. Obs. Structure Mass Structure Mass

430.2

430.2

470.3

497.3

470.3

459.3

442.2

459.3

430.2

443.2

443.2

424.2

444.2

429.2

430.2

443.2

448.3

443.2

460.3

419.2

447.3

420.2

463.3

436.2

454.3

407.2

443.2

Human Cathepsin D FRET Assay

The substrate used below has been described (Y. Yasuda et al., J.Biochem., 125, 1137 (1999)). Substrate and enzyme are commerciallyavailable.

The assay can be run in a 30 μl final volume using a 384 well Nunc blackplate. 8 concentrations of compound can be pre-incubated with enzyme for30 mins at 37° C. followed by addition of substrate with continuedincubation at 37° C. for 45 mins. The rate of increase in fluorescenceis linear for over 1 h and is measured at the end of the incubationperiod using a Molecular Devices FLEX station plate reader. Kis areinterpolated from the IC₅₀s using a Km value of 4 μM and the substrateconcentration of 2.5 μM.

Reagents

-   Na-Acetate pH 5-   1% Brij-35 from 10% stock (Calbiochem)-   DMSO-   Purified (>95%) human liver Cathepsin D (Athens Research &    Technology Cat# 16-12-030104)-   Peptide substrate (Km=4 uM)    Mca-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys(Dnp)-D-Arg-NH₂ Bachem    Cat # M-2455-   Pepstatin is used as a control inhibitor (Ki˜0.5 nM) and is    available from Sigma.-   Nunc 384 well black plates    Final Assay Buffer Conditions-   100 mM Na Acetate pH 5.0-   0.02% Brij-35-   1% DMSO

Compound can be diluted to 3× final concentration in assay buffercontaining 3% DMSO. 10 μl of compound will be added to 10 μl of 2.25 nMenzyme (3×) diluted in assay buffer without DMSO, mixed briefly, spun,and can be incubated at 37° C. for 30 mins. 3× substrate (7.5 μM) isprepared in 1× assay buffer without DMSO. 10 μl of substrate will beadded to each well mixed and spun briefly to initiate the reaction.Assay plates can be incubated at 37 C for 45 mins and read on 384compatible fluorescence plate reader using a 328 nm Ex and 393 nm Em.

BACE-1 Cloning, Protein Expression and Purification

A predicted soluble form of human BACE1 (sBACE1, corresponding to aminoacids 1-454) can be generated from the full length BACE1 cDNA (fulllength human BACE1 cDNA in pCDNA4/mycHisA construct; University ofToronto) by PCR using the advantage-GC cDNA PCR kit (Clontech, PaloAlto, Calif.). A HindIII/PmeI fragment from pCDNA4-sBACE1 myc/His can beblunt ended using Klenow and subcloned into the Stu I site ofpFASTBACI(A) (Invitrogen). A sBACE1 mycHis recombinant bacmid can begenerated by transposition in DH10Bac cells(GIBCO/BRL). Subsequently,the sBACE1mycHis bacmid construct can be transfected into sf9 cellsusing CellFectin (Invitrogen, San Diego, Calif.) in order to generaterecombinant baculovirus. Sf9 cells are grown in SF 900-II medium(Invitrogen) supplemented with 3% heat inactivated FBS and 0.5×penicillin/streptomycin solution (Invitrogen). Five milliliters of hightiter plaque purified sBACEmyc/His virus is used to infect 1 L oflogarithmically growing sf9 cells for 72 hours. Intact cells arepelleted by centrifugation at 3000×g for 15 minutes. The supernatant,containing secreted sBACE1, is collected and diluted 50% v/v with 100 mMHEPES, pH 8.0. The diluted medium is loaded onto a Q-sepharose column.The Q-sepharose column is washed with Buffer A (20 mM HEPES, pH 8.0, 50mM NaCl).

Proteins, can be eluted from the 0-sepharose column with Buffer B (20 mMHEPES, pH 8.0, 500 mM NaCl). The protein peaks from the Q-sepharosecolumn are pooled and loaded onto a Ni-NTA agarose column. The Ni-NTAcolumn can be then washed with Buffer C (20 mM HEPES, pH 8.0, 500 mMNaCl). Bound proteins are then eluted with Buffer D (Buffer C+250 mMimidazole). Peak protein fractions as determined by the Bradford Assay(Biorad, Calif.) are concentrated using a Centricon 30 concentrator(Millipore). sBACE1 purity is estimated to be ˜90% as assessed bySDS-PAGE and Commassie Blue staining. N-terminal sequencing indicatesthat greater than 90% of the purified sBACE1 contained the prodomain;hence this protein is referred to as sproBACE1.

Peptide Hydrolysis Assay

The inhibitor, 25 nM EuK-biotin labeled APPsw substrate(EuK-KTEEISEVNLDAEFRHDKC-biotin (SEQ ID NO: 1); CIS-Bio International,France), 5 μM unlabeled APPsw peptide (KTEEISEVNLDAEFRHDK; (SEQ ID NO:2) American Peptide Company, Sunnyvale, Calif.), 7 nM sproBACE1, 20 mMPIPES pH 5.0, 0.1% Brij-35 (protein grade, Calbiochem, San Diego,Calif.), and 10% glycerol were preincubated for 30 min at 30° C.Reactions were initiated by addition of substrate in a 5 μl aliquotresulting in a total volume of 25 μl. After 3 hr at 30° C. reactionswere terminated by addition of an equal volume of 2× stop buffercontaining 50 mM Tris-HCl pH 8.0, 0.5 M KF, 0.001% Brij-35, 20 μg/mlSA-XL665 (cross-linked allophycocyanin protein coupled to streptavidin;CIS-Bio International, France) (0.5 μg/well). Plates were shaken brieflyand spun at 1200×g for 10 seconds to pellet all liquid to the bottom ofthe plate before the incubation. HTRF measurements were made on aPackard Discovery® HTRF plate reader using 337 nm laser light to excitethe sample followed by a 50 μs delay and simultaneous measurements ofboth 620 nm and 665 nm emissions for 400 μs.

IC₅₀ determinations for inhibitors, (I), are determined by measuring thepercent change of the relative fluorescence at 665 nm divided by therelative fluorescence at 620 nm, (665/620 ratio), in the presence ofvarying concentrations of I and a fixed concentration of enzyme andsubstrate. Nonlinear regression analysis of this data can be performedusing GraphPad Prism 3.0 software selecting four parameter logisticequation, that allows for a variable slope.Y=Bottom+(Top-Bottom)/(1+10^((LogEC50−X)*Hill Slope)); X is thelogarithm of concentration of I, Y is the percent change in ratio and Ystarts at bottom and goes to top with a sigmoid shape.

Using the above assay, the K_(i) values of some of the compounds weredetermined. The K_(i) values ranged from 0.1 to 100,000 nM.

Human Mature Renin Enzyme Assay

Human Renin can be cloned from a human kidney cDNA library andC-terminally epitope-tagged with the V5-6His sequence into pCDNA3.1.pCNDA3.1-Renin-V5-6His is stably expressed in HEK293 cells and purifiedto >80% using standard Ni-Affinity chromatography. The prodomain of therecombinant human renin-V5-6His can be removed by limited proteolysisusing immobilized TPCK-trypsin to give mature-human renin. Reninenzymatic activity can be monitored using a commercially availablefluorescence resonance energy transfer (FRET) peptide substrate, RS-1(Molecular Probes, Eugene, Oreg.) in 50 mM Tris-HCl pH 8.0, 100 mM NaCl,0.1% Brij-35 and 5% DMSO buffer for 40 mins at 30° Celsius in thepresence or absence of different concentrations of test compounds.Mature human Renin is present at approximately 200 nM. Inhibitoryactivity is defined as the percent decrease in renin inducedfluorescence at the end of the 40 min incubation compared to vehiclecontrols and samples lacking enzyme.

In the aspect of the invention relating to a combination of at least onecompound of formula I with at least one cholinesterase inhibitor,acetyl- and/or butyrylcholinesterase inhibitors can be used. Examples ofcholinesterase inhibitors are tacrine, donepezil, rivastigmine,galantamine, pyridostigmine and neostigmine, with tacrine, donepezil,rivastigmine and galantamine being preferred. Preferably, thesecombinations are directed to the treatment of Alzheimer's Disease.

In one aspect of the invention, a combination of at least one compoundof formula I with at least one muscarinic m₁ agonist or m₂ antagonistcan be used. Examples of m₁ agonists are known in the art. Examples ofm₂ antagonists are also known in the art; in particular, m₂ antagonistsare disclosed in U.S. Pat. Nos. 5,883,096; 6,037,352; 5,889,006;6,043,255; 5,952,349; 5,935,958; 6,066,636; 5,977,138; 6,294,554;6,043,255; and 6,458,812; and in WO 03/031412, all of which areincorporated herein by reference.

In other aspects of the invention relating to a combination of at leastone compound of formula I and at least one other agent, for example abeta secretase inhibitor; a gamma secretase inhibitor; an HMG-CoAreductase inhibitor such as atorvastatin, lovastatin, simvastatin,pravastatin, fluvastatin and rosuvastatin; non-steroidalanti-inflammatory agents such as, but not necessarily limited toibuprofen, relafen or naproxen; N-methyl-D-aspartate receptorantagonists such as memantine; anti-amyloid antibodies includinghumanized monoclonal antibodies; vitamin E; nicotinic acetylcholinereceptor agonists; CB1 receptor inverse agonists or CB1 receptorantagonists; antibiotics such as doxycycline; growth hormonesecretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors;GABA_(A) inverse agonists; inhibitors of amyloid aggregation; glycogensynthase kinase beta inhibitors; promoters of alpha secretase activity.Preferably, these combinations are directed to the treatment ofAlzheimer's Disease.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18th Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 100 mg, preferably fromabout 1 mg to about 50 mg, more preferably from about 1 mg to about 25mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 300 mg/day, preferably 1 mg/day to 50 mg/day, in two tofour divided doses.

When a compound of formula I is used in combination with acholinesterase inhibitor to treat cognitive disorders, these two activecomponents may be co-administered simultaneously or sequentially, or asingle pharmaceutical composition comprising a compound of formula I anda cholinesterase inhibitor in a pharmaceutically acceptable carrier canbe administered. The components of the combination can be administeredindividually or together in any conventional oral or parenteral dosageform such as capsule, tablet, powder, cachet, suspension, solution,suppository, nasal spray, etc. The dosage of the cholinesteraseinhibitor can be determined from published material, and may range from0.001 to 100 mg/kg body weight.

When separate pharmaceutical compositions of a compound of formula I anda cholinesterase inhibitor are to be administered, they can be providedin a kit comprising in a single package, one container comprising acompound of formula I in a pharmaceutically acceptable carrier, and aseparate container comprising a cholinesterase inhibitor in apharmaceutically acceptable carrier, with the compound of formula I andthe cholinesterase inhibitor being present in amounts such that thecombination is therapeutically effective. A kit is advantageous foradministering a combination when, for example, the components must beadministered at different time intervals or when they are in differentdosage forms.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1. A compound having the following structure:

or a stereoisomer, tautomer, or pharmaceutically acceptable salt of saidcompound, said stereoisomer, or said tautomer, wherein: b is 1; c is 1,W is —C(═S)—, —C(═O)—, —C(R⁶)(R⁷)—, —C(R⁶)(R⁷)C(═O)—, or —C(═N(R⁵))—; Ris absent or 1 to 5 R²¹ groups; R¹, and R⁵ are independently selectedfrom the group consisting of H, alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, —OR¹⁵, —CN,—C(═NR¹¹)R⁸, —C(O)R⁸, —C(O)OR⁹, —S(O)R¹⁰, —S(O)₂R¹⁰, —C(O)N(R¹¹)(R¹²),—S(O)N(R¹¹)(R¹²), —S(O)₂N(R¹¹)(R¹²), —NO₂, —N═C(R⁸)₂ and —N(R¹¹)(R¹²),wherein each of the alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl in R⁵ is unsubstituted or substituted by 1to 5 R²¹ groups; R² is selected from the group consisting of H, aryl,and aryl substituted by 1 to 5 R²¹ groups; R³ and R⁷ are independentlyselected from the group consisting of H, alkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CH₂—O—Si(R⁹)(R¹⁰)(R¹⁹), —SH, —CN,—OR⁹, —C(O)R⁸, —C(O)OR⁹, —C(O)N(R¹¹)(R¹²), —SR¹⁹, —S(O)N(R¹¹)(R¹²),—S(O)₂N(R¹¹)(R¹²), —N(R¹¹)(R¹²), —(R¹¹)C(O)R⁸, —N(R¹¹)S(O)R¹⁰,—N(R¹¹)S(O)₂R¹⁰, —N(R¹¹)C(O)N(R¹²)(R¹³), —N(R¹¹)C(O)OR⁹ and —C(═NOH)R⁸;R⁶ is selected from the group consisting of aryl, (R²¹)₁₋₅-aryl,thiophenyl, and (R²¹)₁₋₃-thiophenyl; R⁸ is independently selected fromthe group consisting of H, alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, —OR¹⁵,—N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶,—N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷)and —N(R¹⁵)C(O)OR¹⁶; R⁹ is independently selected from the groupconsisting of H, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl, andheterocycloalkenylheteroaryl; R¹⁰ is independently selected from thegroup consisting of H, alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, aryl heterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl and —N(R¹⁵)(R¹⁶);R¹¹, R¹², and R¹³ are independently selected from the group consistingof H, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —C(O)R⁸, —C(O)OR⁹, —S(O)R¹⁰, —S(O)₂R¹⁰,—C(O)N(R¹⁵)(R¹⁶), —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶) and —CN; R¹⁵, R¹⁶and R¹⁷ are independently selected from the group consisting of H,alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,aryl heterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, R¹⁸-alkyl, R¹⁸-arylalkyl,R¹⁸-heteroarylalkyl, R¹⁸-cycloalkylalkyl, R¹⁸-heterocycloalkylalkyl,R¹⁸-arylcycloalkylalkyl, R¹⁸-heteroarylcycloalkylalkyl,R¹⁸-arylheterocycloalkylalkyl, R¹⁸-heteroarylheterocycloalkylalkyl,R¹⁸-cycloalkyl, R¹⁸-arylcycloalkyl, R¹⁸-heteroarylcycloalkyl,R¹⁸-heterocycloalkyl, R¹⁸-arylheterocycloalkyl,R¹⁸-heteroarylheterocycloalkyl, R¹⁸-alkenyl, R¹⁸-arylalkenyl,R¹⁸-cycloalkenyl, R¹⁸-arylcycloalkenyl, R¹⁸-heteroarylcycloalkenyl,R¹⁸-heterocycloalkenyl, R¹⁸-arylheterocycloalkenyl,R¹⁸-heteroarylheterocycloalkenyl, R¹⁸-alkynyl, R¹⁸-arylalkynyl,R¹⁸-aryl, R¹⁸-cycloalkylaryl, R¹⁸-heterocycloalkylaryl,R¹⁸-cycloalkenylaryl, R¹⁸-heterocycloalkenylaryl, R¹⁸-heteroaryl,R¹⁸-cycloalkylheteroaryl, R¹⁸-heterocycloalkylheteroaryl,R¹⁸-cycloalkenylheteroaryl, and R¹⁸-heterocycloalkenylheteroaryl; orR¹⁵, R¹⁶ and R¹⁷ are

wherein R²³ numbers 0 to 5 substituents, m is 0 to 6 and n is 0 to 5;R¹⁸ is 1-5 substituents independently selected from the group consistingof alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —NO₂, halo, HO-alkoxyalkyl, —CF₃, —ON,alkyl-CN, —C(O)R¹⁹, —C(O)OH, —C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂,—C(O)NH₂—C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl),—SR¹⁹, —S(O)₂R²⁰, —S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl),—S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocycloalkyl),—S(O)₂N(alkyl)₂, —S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰,—O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂,—NHR²⁰, —N(alkyl)₂, —N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl),—NHC(O)R²⁰, —NHC(O)NH₂, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl),—N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰,—NHS(O)₂NH(alkyl), —NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl); or two R¹⁸ moieties on adjacent carbonscan be linked together to form

R¹⁹ is alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl orheterocycloalkenylheteroaryl; R²⁰ is halo substituted aryl, alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl orheterocycloalkenylheteroaryl; each R²¹ group is independently selectedfrom the group consisting of alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl, heteroarylcycloalkyl,heterocycloalkyl, arylheterocycloalkyl, heteroarylheterocycloalkyl,alkenyl, arylalkenyl, cycloalkenyl, arylcycloalkenyl,heteroarylcycloalkenyl, heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CN, —C(═NR¹¹)R¹⁵, —OR¹⁵, —C(O)R¹⁵,—C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),-alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶,—S(O)R¹⁵, —N₃, —NO₂ and —S(O)₂R¹⁵; and wherein each of the alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroaryl heterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl andheterocycloalkenylheteroaryl groups in R²¹ are independentlyunsubstituted or substituted by 1 to 5 R²² groups; each R²² group isindependently selected from the group consisting of alkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CF₃, —CN, —C(═NR¹¹)R¹⁵, —OR¹⁵,—C(O)R¹⁵, —C(O)OR¹⁵, -alkyl-C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵,—S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —(P(O)(OR¹⁵)(OR¹⁶),—N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,—N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶,—N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃,—NO₂, —S(O)R¹⁵ and —S(O)₂R¹⁵; or two R²¹ or two R²² moieties on adjacentcarbons can be linked together to form

and when R²¹ or R²² are selected from the group consisting of—C(═NOR¹⁵)R¹⁶, —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶ and —CH₂—N(R¹⁵)C(O)OR¹⁶, R¹⁵and R¹⁶ together can be a C₂ to C₄ chain wherein, optionally, one, twoor three ring carbons can be replaced by —C(O)— or —N(H)— and R¹⁵ andR¹⁶, together with the atoms to which they are attached, form a 5 to 7membered ring, optionally substituted by R²³; R²³ is 0 to 5 groupsindependently selected from the group consisting of alkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, aryl heterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CN, —OR²⁴, —C(O)R²⁴, —C(O)OR²⁴,—C(O)N(R²⁴)(R²⁵), —SR²⁴, —S(O)N(R²⁴)(R²⁵) —S(O)₂N(R²⁴)(R²⁵),—C(═NOR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵), —N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵),—N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵, —N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵,—CH₂—N(R²⁴)S(O)₂R²⁵, —N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴; and wherein each of thealkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl andheterocycloalkenylheteroaryl groups in R²³ are independentlyunsubstituted or substituted by R²⁷; R²⁴, R²⁵ and R²⁶ are independentlyselected from the group consisting of H, alkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, R²⁷-alkyl, R²⁷-arylalkyl,R²⁷-heteroarylalkyl, R²⁷-cycloalkylalkyl, R²⁷-heterocycloalkylalkyl,R²⁷-arylcycloalkylalkyl, R²⁷-heteroarylcycloalkylalkyl,R²⁷-arylheterocycloalkylalkyl, R²⁷-heteroarylheterocycloalkylalkyl,R²⁷-cycloalkyl, R²⁷-arylcycloalkyl, R²⁷-heteroarylcycloalkyl,R²⁷-heterocycloalkyl, R²⁷-aryl heterocycloalkyl,R²⁷-heteroarylheterocycloalkyl, R²⁷-alkenyl, R²⁷-arylalkenyl,R²⁷-cycloalkenyl, R²⁷-arylcycloalkenyl, R²⁷-heteroarylcycloalkenyl,R²⁷-heterocycloalkenyl, R²⁷-arylheterocycloalkenyl,R²⁷-heteroarylheterocycloalkenyl, R²⁷-alkynyl, R²⁷-arylalkynyl,R²⁷-aryl, R²⁷-cycloalkylaryl, R²⁷-heterocycloalkylaryl,R²⁷-cycloalkenylaryl, R²⁷-heterocycloalkenylaryl, R²⁷-heteroaryl,R²⁷-cycloalkylheteroaryl, R²⁷-heterocycloalkylheteroaryl,R²⁷-cycloalkenylheteroaryl and R²⁷-heterocycloalkenylheteroaryl; R²⁷ is1-5 substituents independently selected from the group consisting ofalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —NO₂, halo, —CF₃, —CN, alkyl-CN, —C(O)R²⁸,—C(O)OH, —C(O)OR²⁸, —C(O)NHR²⁹, —C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl),—C(O)N(alkyl)(heteroaryl), —SR²⁸, —S(O)₂R²⁹, —S(O)NH₂, —S(O)NH(alkyl),—S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR²⁸,—S(O)₂NH(aryl), —S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OH, —OR²⁹, —O-heterocycloalkyl,—O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂, —NHR²⁹, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R²⁹, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁹, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl); R²⁸ is alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, aryl heterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl, cycloalkenylheteroarylor heterocycloalkenylheteroaryl; R²⁹ is alkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl orheterocycloalkenylheteroaryl, wherein: “heteroaryl” means a moietyselected from pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl,isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridinyl,imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl,benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl,quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl,isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, and benzothiazolyl;“heterocyclyl” (or “heterocycloalkyl”) means a moiety selected frompiperidyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, piperazinyl,morpholinyl, thiomorpholinyl, dithianyl, trithianyl, thiazolidinyl,1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl,and tetrahydrothiopyranyl; and “heterocyclenyl” (or “hetocyloalkenyl”)means a heterocyclyl moiety as defined above which contains at least onecarbon-carbon double bond and/or at least one carbon-nitrogen doublebond.
 2. A compound of claim 1, wherein: R is absent.
 3. A compound ofclaim 1, wherein: R is 1 to 5 R²¹ groups.
 4. A compound of claim 1,wherein: R¹ is alkyl.
 5. A compound of claim 1, wherein: R¹ is methyl.6. A compound of claim 1, wherein: R² is H.
 7. A compound of claim 1,wherein: R³ is H.
 8. A compound having the following structure:

or a stereoisomer, tautomer, or pharmaceutically acceptable salt of saidcompound, said stereoisomer, or said tautomer, wherein: R⁵ is selectedfrom the group consisting of H, alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, —OR¹⁵, —CN,—C(═NR¹¹)R⁸, —C(O)R⁸, —C(O)OR⁹, —S(O)R¹⁰, —S(O)₂R¹⁰, —C(O)N(R¹¹)(R¹²),—S(O)N(R¹¹)(R¹²), —S(O)₂N(R¹¹)(R¹²), —NO₂, —N═C(R⁸)₂ and —N(R¹¹)(R¹²),wherein each of the alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl in R⁵ is unsubstituted or substituted by 1to 5 R²¹ groups; R⁶ is selected from the group consisting of aryl,(R²¹)₁₋₅-aryl, thiophenyl, and (R²¹)₁₋₃-thiophenyl; R⁸ is independentlyselected from the group consisting of H, alkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —OR¹⁵, —N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶,—N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) and —N(R¹⁵)C(O)OR¹⁶; R⁹is independently selected from the group consisting of H, alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl, andheterocycloalkenylheteroaryl; R¹⁰ is independently selected from thegroup consisting of H, alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl and —N(R¹⁵)(R¹⁶);R¹¹ and R¹² are each independently selected from the group consisting ofH, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —C(O)R⁸, —C(O)OR⁹, —S(O)R¹⁰, —S(O)₂R¹⁰,—C(O)N(R¹⁵)(R¹⁶), —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶) and —CN; R¹⁵, R¹⁶and R¹⁷ are independently selected from the group consisting of H,alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, R¹⁸-alkyl, R¹⁸-arylalkyl,R¹⁸-heteroarylalkyl, R¹⁸-cycloalkylalkyl, R¹⁸-heterocycloalkylalkyl,R¹⁸-arylcycloalkylalkyl, R¹⁸-heteroarylcycloalkylalkyl,R¹⁸-arylheterocycloalkylalkyl, R¹⁸-heteroarylheterocycloalkylalkyl,R¹⁸-cycloalkyl, R¹⁸-arylcycloalkyl, R¹⁸-heteroarylcycloalkyl,R¹⁸-heterocycloalkyl, R¹⁸-arylheterocycloalkyl,R¹⁸-heteroarylheterocycloalkyl, R¹⁸-alkenyl, R¹⁸-arylalkenyl,R¹⁸-cycloalkenyl, R¹⁸-arylcycloalkenyl, R¹⁸-heteroarylcycloalkenyl,R¹⁸-heterocycloalkenyl, R¹⁸-arylheterocycloalkenyl,R¹⁸-heteroarylheterocycloalkenyl, R¹⁸-alkynyl, R¹⁸-arylalkynyl,R¹⁸-aryl, aryl, R¹⁸-cycloalkylaryl, R¹⁸-heterocycloalkylaryl,R¹⁸-cycloalkenylaryl, R¹⁸-heterocycloalkenylaryl, R¹⁸-heteroaryl,R¹⁸-cycloalkylheteroaryl, R¹⁸-heterocycloalkylheteroaryl,R¹⁸-cycloalkenylheteroaryl, and R¹⁸-heterocycloalkenylheteroaryl; orR¹⁵, R¹⁶ and R¹⁷ are

wherein R²³ numbers 0 to 5 substituents, m is 0 to 6 and n is 0 to 5;R¹⁸ is 1-5 substituents independently selected from the group consistingof alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —NO₂, halo, HO-alkoxyalkyl, —CF₃, —CN,alkyl-CN, —C(O)R¹⁹, —C(O)OH, —C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂,—C(O)NH₂—C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl),—SR¹⁹, —S(O)₂R²⁰, —S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl),—S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocycloalkyl),—S(O)₂N(alkyl)₂, —S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰,—O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂,—NHR²⁰, —N(alkyl)₂, —N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl),—NHC(O)R²⁰, —NHC(O)NH₂, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl),—N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰,—NHS(O)₂NH(alkyl), —NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl); or two R¹⁸ moieties on adjacent carbonscan be linked together to form

R¹⁹ is alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,aryl heterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl orheterocycloalkenylheteroaryl; R²⁰ is halo substituted aryl, alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl orheterocycloalkenylheteroaryl; each R²¹ group is independently selectedfrom the group consisting of alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, aryl heterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, halo, —CN,—C(═NR¹¹)R¹⁵, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵,—S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶,—P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵;—CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶,—N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶,—S(O)R¹⁵, —N₃, —NO₂ and —S(O)₂R¹⁵; and wherein each of the alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl andheterocycloalkenylheteroaryl groups in R²¹ are independentlyunsubstituted or substituted by 1 to 5 R²² groups; each R²² group isindependently selected from the group consisting of alkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CF₃, —CN, —C(═NR¹¹)R¹⁵, —OR¹⁵,C(O)R¹⁵, —C(O)OR¹⁵, -alkyl-C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵,—S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶),—N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,—N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶,—N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃,—NO₂, —S(O)R¹⁵ and —S(O)₂R¹⁵; or two R²¹ or two R²² moieties on adjacentcarbons can be linked together to form

and when R²¹ or R²² are selected from the group consisting of—C(═NOR¹⁵)R¹⁶, —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶ and —CH₂—N(R¹⁵)C(O)OR¹⁶, R¹⁵and R¹⁶ together can be a C₂ to C₄ chain wherein, optionally, one, twoor three ring carbons can be replaced by —C(O)— or —N(H)— and R¹⁵ andR¹⁶, together with the atoms to which they are attached, form a 5 to 7membered ring, optionally substituted by R²³; R²³ is 0 to 5 groupsindependently selected from the group consisting of alkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CN, —OR²⁴, —C(O)R²⁴, —C(O)OR²⁴,—C(O)N(R²⁴)(R²⁵), —SR²⁴, —S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵),—C(═NOR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵), —N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵),—N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵, —N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵,—CH₂—N(R²⁴)S(O)₂R²⁵, —N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴; and wherein each of thealkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl, cycloalkylaryl,heterocycloalkylaryl, cycloalkenylaryl, heterocycloalkenylaryl,heteroaryl, cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl and heterocycloalkenylheteroaryl groups in R²³are independently unsubstituted or substituted by R²⁷; R²⁴, R²⁵ and R²⁶are independently selected from the group consisting of H, alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, R²⁷-alkyl, R²⁷-arylalkyl,R²⁷-heteroarylalkyl, R²⁷-cycloalkylalkyl, R²⁷-heterocycloalkylalkyl,R²⁷-arylcycloalkylalkyl, R²⁷-heteroarylcycloalkylalkyl,R²⁷-arylheterocycloalkylalkyl, R²⁷-heteroarylheterocycloalkylalkyl,R²⁷-cycloalkyl, R²⁷-arylcycloalkyl, R²⁷-heteroarylcycloalkyl,R²⁷-heterocycloalkyl, R²⁷-arylheterocycloalkyl,R²⁷-heteroarylheterocycloalkyl, R²⁷-alkenyl, R²⁷-arylalkenyl,R²⁷-cycloalkenyl, R²⁷-arylcycloalkenyl, R²⁷-heteroarylcycloalkenyl,R²⁷-heterocycloalkenyl, R²⁷-arylheterocycloalkenyl,R²⁷-heteroarylheterocycloalkenyl, R²⁷-alkynyl, R²⁷-arylalkynyl,R²⁷-aryl, R²⁷-cycloalkylaryl, R²⁷-heterocycloalkylaryl,R²⁷-cycloalkenylaryl, R²⁷-heterocycloalkenylaryl, R²⁷-heteroaryl,R²⁷-cycloalkylheteroaryl, R²⁷-heterocycloalkylheteroaryl,R²⁷-cycloalkenylheteroaryl and R²⁷-heterocycloalkenylheteroaryl; R²⁷ is1-5 substituents independently selected from the group consisting ofalkyl, aryl alkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —NO₂, halo, —CF₃, —CN, alkyl-CN, —C(O)R²⁸,—C(O)OH, —C(O)OR²⁸, —C(O)NHR²⁹, —C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl),—C(O)N(alkyl)(heteroaryl), —SR²⁸, —S(O)₂R²⁹, —S(O)NH₂, —S(O)NH(alkyl),—S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR²⁸,—S(O)₂NH(aryl), —S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OH, —OR²⁹, —O-heterocycloalkyl,—O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂, —NHR²⁹, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R²⁹, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁹, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl); R²⁸ is alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl, cycloalkenylheteroarylor heterocycloalkenylheteroaryl; R²⁹ is alkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl orheterocycloalkenylheteroaryl, wherein: “heteroaryl” means a moietyselected from pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl,isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridinyl,imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl,benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl,quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl,isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, and benzothiazolyl;“heterocyclyl” (or “heterocycloalkyl”) means a moiety selected frompiperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl,thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, and tetrahydrothiopyranyl; and “heterocyclenyl”(or “hetocyloalkenyl”) means a heterocyclyl moiety as defined abovewhich contains at least one carbon-carbon double bond and/or at leastone carbon-nitrogen double bond.
 9. A compound of claim 8, wherein: R²¹is


10. A compound of claim 8, wherein: R⁶ is


11. A compound of claim 8, wherein: R⁶ is aryl.
 12. A compound of claim8, wherein: R⁶ is (R²¹)₁₋₅-aryl.
 13. A compound of claim 12, wherein:R²¹ is —CN, halo, aryl, (R²²)-aryl, heteroaryl, or (R²²)₁₋₂-heteroaryl.14. A compound of claim 13, wherein: R²² is —CN, halo or alkyne.
 15. Acompound of claim 14, wherein: R²² is F or


16. A compound of claim 13, wherein: R²¹ is halo.
 17. A compound ofclaim 8, wherein: R⁶ is


18. A compound of claim 8, wherein: R⁶ is


19. A compound of claim 18, wherein: R²¹ is —CN, halo, aryl, (R²²)-aryl,heteroaryl, or (R²²)₁₋₂-heteroaryl.
 20. A compound of claim 19, wherein:R²¹ is halo.
 21. A compound of claim 8, wherein: R⁶ is selected from thegroup consisting of thiophenyl and (R²¹)₁₋₃-thiophenyl.
 22. A compoundof claim 8, wherein: R⁶ is


23. A compound of claim 8, wherein: R⁶ is (R²¹)₁₋₃-thiophenyl.
 24. Acompound of claim 23, wherein: R²¹ is —CN, halo, aryl, (R²²)-aryl,heteroaryl, or (R²²)₁₋₂-heteroaryl.
 25. A compound of claim 24, wherein:R²¹ is halo.
 26. A compound of claim 8, wherein: R⁶ is


27. A compound of claim 26, wherein: R²¹ is —CN, halo, aryl, (R²²)-aryl,heteroaryl, or (R²²)₁₋₂-heteroaryl.
 28. A compound of claim 27, wherein:R²¹ is halo.
 29. A compound of claim 8, wherein: R⁵ is selected from thegroup consisting of arylalkyl, aryl, heteroaryl, —C(═NR¹¹)R⁸, —C(O)R⁸,C(O)OR⁹, aryl-R²¹ and heteroaryl-R²¹.
 30. A compound of claim 29,wherein R⁵ is


31. A compound of claim 29, wherein R⁸ and R⁹ are independently selectedfrom the group consisting of: alkyl, cycloalkyl, aryl, arylalkyl,heteroaryl, R¹⁸-alkyl, R¹⁸-aryl, and R¹⁸-heteroaryl.
 32. A compound ofclaim 30, wherein R⁸ and R⁹ are independently selected from the groupconsisting of:


33. A compound of claim 31, wherein R¹⁸ is 1-5 substituentsindependently selected from the group consisting of alkyl, halo, —CF₃,—CN, —SR¹⁹ and —OR²⁰.
 34. A compound of claim 31, wherein R¹⁸ is 1-5substituents independently selected from the group consisting of halo,—CN, —OCH(CH₃)₂, —OCH₃, —CH₃,


35. A compound of claim 29, wherein R⁵ is aryl-R²¹.
 36. A compound ofclaim 35, wherein R²¹ is 1-5 substituents independently selected fromthe group consisting of halo, —OCH(CH₃)₂, —CH₃, —CF₃, —OCH₃, —CH(CH₃)₂and —CN.
 37. A compound of claim 29, wherein R⁵ is heteroaryl-R²¹.
 38. Acompound of claim 37, wherein R²¹ is 1-5 substituents independentlyselected from the group consisting of halo, —OCH(CH₃)₂, —CH₃, —CF₃,—OCH₃, —CH(CH₃)₂ and —CN.
 39. A compound, or a stereoisomer, tautomer,or pharmaceutically acceptable salt of said compound, said stereoisomer,or said tautomer, selected from the group consisting of:


40. A compound, or a stereoisomer, tautomer, or pharmaceuticallyacceptable salt of said compound, said stereoisomer, or said tautomer,selected from the group consisting of:


41. A pharmaceutical composition comprising at least one compound ofclaim 1 and a pharmaceutically effective carrier.
 42. A pharmaceuticalcomposition comprising at least one compound of claim 8 and apharmaceutically effective carrier.
 43. A pharmaceutical compositioncomprising at least one compound of claim 29 and a pharmaceuticallyeffective carrier.
 44. A pharmaceutical composition comprising at leastone compound of claim 39 and a pharmaceutically effective carrier.
 45. Apharmaceutical composition comprising at least one compound of claim 40and a pharmaceutically effective carrier.